Stem Cell-Derived Cells Market To Witness A Considerable CAGR Growth Through The Forecast Period 2019 2029 – 3rd Watch News

New Study on the Global Stem Cell-Derived Cells Market by PMR

PMR recently published a market study that sheds light on the growth prospects of the global Stem Cell-Derived Cells market during the forecast period (20XX-20XX). In addition, a methodical and systematic approach adopted by the analysts while curating the market study ensures that the presented study adds value to the business of our customers. The report provides a thorough evaluation of the latest trends, market drivers, opportunities, and challenges within the global Stem Cell-Derived Cells market.

As per the report, the global Stem Cell-Derived Cells market is expected to grow at a CAGR of ~XX% during the stipulated timeframe owing to a range of factors including, favorable government policies, and growing awareness related to the Stem Cell-Derived Cells , surge in research and development and more.

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Resourceful insights enclosed in the report:

Competitive Outlook

The competitive outlook section provides valuable information related to the different companies operating in the current Stem Cell-Derived Cells market landscape. The market share, product portfolio, pricing strategy, sales and distribution channels of each company is discussed in the report.

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Regional Assessment

The presented market study touches upon the market scenario in different regions and provides a deep understanding of the influence of micro and macro-economic factors on the prospects of the market in each region.

key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

The report covers exhaustive analysis on:

Regional analysis includes

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Stem Cell-Derived Cells Market To Witness A Considerable CAGR Growth Through The Forecast Period 2019 2029 - 3rd Watch News

Decoding the Relationship Between Ageing and ALS – Medscape

Abstract and Introduction Abstract

With an ageing population comes an inevitable increase in the prevalence of age-associated neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a relentlessly progressive and universally fatal disease characterized by the degeneration of upper and lower motor neurons within the brain and spinal cord. Indeed, the physiological process of ageing causes a variety of molecular and cellular phenotypes. With dysfunction at the neuromuscular junction implicated as a key pathological mechanism in ALS, and each lower motor unit cell type vulnerable to its own set of age-related phenotypes, the effects of ageing might in fact prove a prerequisite to ALS, rendering the cells susceptible to disease-specific mechanisms. Moreover, we discuss evidence for overlap between age and ALS-associated hallmarks, potentially implicating cell type-specific ageing as a key contributor to this multifactorial and complex disease. With a dearth of disease-modifying therapy currently available for ALS patients and a substantial failure in bench to bedside translation of other potential therapies, the unification of research in ageing and ALS requires high fidelity models to better recapitulate age-related human disease and will ultimately yield more reliable candidate therapeutics for patients, with the aim of enhancing healthspan and life expectancy.

The human population is ageing, with an estimated 1.5 billion people expected to be 65+ years by 2050, triple the 2010 estimate (World Health Organisation, 2011). But alongside a lengthened life expectancy comes the drawback of age-related ill health that compromises quality of life. Ageing is a ubiquitous phenomenon, with multiple hypotheses attempting to explain why age-related changes occur on an organism, organ and cellular level (reviewed in Jin, 2010; Lopez-Otin et al., 2013) (Figure 1). Indeed, age is the most prevalent risk factor for neurodegenerative disease (reviewed in Khan et al., 2017). Within this group is amyotrophic lateral sclerosis (ALS), a relentlessly progressive and universally fatal disease underpinned by degeneration of motor neurons. With a prognosis of 25 years from onset to fatality and a myriad of complex debilitating symptoms (reviewed in Balendra and Patani, 2016), it is key to elucidate the true pathogenic mechanisms underlying ALS and use these insights to develop truly impactful disease-modifying therapies for patients, a feat yet to be achieved.

Figure 1.

Human ageing theories and phenotypes. A number of theories aim to explain human ageing (reviewed in Jin, 2010), broadly categorized into the programmed theories of ageing, where normal ageing follows a set biological clock with time-dependent expression changes, and damage theories of ageing, where accumulation of damage over time ultimately leads to dysfunction (reviewed in Jin, 2010). Age-related abnormalities (described above) are apparent in several organs (reviewed in Khan et al., 2017); however, differential resistance/vulnerability to the effects of ageing in various organs has been noted (reviewed in Khan et al., 2017). The rate of ageing differs between individuals, with some people ageing better and some worse than expected in a phenomenon termed Delta ageing (Rhinn and Abeliovich, 2017). Indeed, variability of ageing rate might also occur on a cellular and organ level, somewhat providing evidence for the mechanism behind cell type and organ specific susceptibility to the effects of ageing, and in turn age-related disease, such as ALS. Templates used/adapted to create this figure are freely available from Servier Medical Art (https://smart.servier.com/).

Several studies have implicated the neuromuscular junction (NMJ), the site of union between motor neuron and muscle within the lower motor unit (Figure 2), in ALS pathogenesis. Indeed, the die-back hypothesis of ALS suggests that motor neuron terminals at the NMJ are the initial foci of pathogenesis with retrograde axonal degeneration ultimately reaching the motor neuron soma, leading to neuronal degeneration and subsequent symptoms (reviewed in Dadon-Nachum et al., 2011). Neuromuscular transmission defects and synaptic aberrance have been shown to precede motor neuron degeneration and motor symptoms in rodent (Rocha et al., 2013; Chand et al., 2018) and fruit fly (Shahidullah et al., 2013) models of ALS. Furthermore, restricting expression of ALS-associated human superoxide dismutase 1 (SOD1) to skeletal muscle, induced motor neuron degeneration and functional defects in transgenic mice overexpressing wild-type human SOD1 or its G93A and G37R mutant forms (Wong and Martin, 2010). This, alongside findings of altered regulation of skeletal muscle specific microRNAs in ALS (reviewed in Di Pietro et al., 2018), fortifies the role of skeletal muscle and the NMJ in ALS pathology, whilst supporting the die-back hypothesis.

Figure 2.

The lower motor unit. Individual components of the lower motor unit: lower motor neuron, skeletal muscle, astrocyte, myelinating Schwann cell, terminal Schwann cell. All constituents of the lower motor unit play key roles in motor function and voluntary movement, are affected by normal ageing and are implicated in ALS pathogenesis. The site of unification of motor neuron and muscle (the neuromuscular junction) has a vital role in ALS pathology and also undergoes age-associated alterations. Templates used/adapted to create this figure are freely available from Servier Medical Art (https://smart.servier.com/).

Here, we review how ageing of the cellular constituents of the lower motor unit relates to ALS. Specifically, we will discuss motor neurons, skeletal muscle, astrocytes and Schwann cells. By integrating insights from these individual components, we discuss the potential role of cell type specific ageing in ALS. Finally, we look at approaches to enhance ALS model fidelity and applicability to patients, as well as potential therapeutic implications of tackling age-associated aberrance, namely maximizing healthspan and lifespan in ALS.

The degeneration of brain and spinal cord motor neurons forms the major pathological substrate of ALS, leading to rapid functional decline and death in patients. As well as the clear contribution of non-neuronal cells to ALS, a number of cell intrinsic motor neuronal pathological hallmarks have been defined, including (but not restricted to) excitotoxicity, abnormal cytoskeleton and axonal transport and disrupted RNA metabolism (reviewed in Van Damme et al., 2017). Indeed, normal ageing bears a variety of structural and functional consequences for motor neurons, which may directly or indirectly contribute to motor neuron pathology in ALS.

Age-related changes in motor neuron number remains a controversial topic, with some studies suggesting motor neuron number and/or size to be stable with ageing in mice and rhesus monkeys (Maxwell et al., 2018), whilst other studies suggest progressive motor neuronal loss [in rat (Jacob, 1998) and human (Tomlinson and Irving, 1977) lumbosacral spinal cords]. Indeed, neither the aged rats nor patients from these studies experienced commensurate loss of physical activity/ability as a result of motor neuron attrition (Tomlinson and Irving, 1977; Jacob, 1998), suggesting a significant functional reserve in this system. Despite not causing outright functional decline, it remains possible however that a reduction in motor neurons with ageing leaves remaining aged motor neurons under elevated stress (Jacob, 1998), and thereby more vulnerable to age-related pathologies, such as ALS.

Voluntary movements depend on effective electrical communication between neurons, with imperative roles for both excitatory (glutamatergic and cholinergic) and inhibitory (GABAergic and glycinergic) synaptic inputs terminating on alpha motor neurons (Maxwell et al., 2018). Indeed, cholinergic synaptic inputs in the ventral horn and specifically those terminating on alpha motor neuron cell bodies were decreased in old rhesus monkeys, a finding mirrored in mice (Maxwell et al., 2018). Glutamatergic synaptic inputs directly terminating on alpha motor neurons in old monkeys and mice were also reduced (Maxwell et al., 2018). Hence, normal ageing is accompanied by loss of synaptic inputs to alpha motor neurons, a key age-related phenotype and indeed, a shared pathological hallmark with motor diseases including ALS [as shown in transactive response DNA binding protein 43kDa (TDP-43) and SOD1 mutant mice] (Vaughan et al., 2015).

Neurons are post-mitotic, meaning they have left the cell cycle and are no longer proliferating, thereby they cannot undergo classical cellular senescence. Emerging literature has however implicated an analogous process in neurons, mimicking some of the key age-related effects of senescence on other cell types. More specifically, human induced pluripotent stem cell (iPSC)-derived neurons from patients with Rett syndrome, characterized by loss-of-function mutations in MECP2, were shown to activate p53, a regulator of cellular senescence, subsequently inhibiting complex neuronal process formation (Ohashi et al., 2018). In addition, senescence-associated secretory phenotype (SASP) genes were also induced and -galactosidase activity increased in neurons lacking MECP2 (Ohashi et al., 2018), indicating that a 'senescence like' picture was present in neurons derived from these patients. It is possible that an analogous senescence process takes place in normal ageing neurons, thus leading to cellular stress, aberrant neuronal health and enhanced vulnerability to further pathological insult.

Lipofuscin aggregates, rich in lipids, metals and misfolded proteins, accumulate in neurons during normal ageing, as well as in other post-mitotic, non-proliferative cell types that lack the capacity to effectively dilute out the aggregates during proliferation (reviewed in Moreno-Garcia et al., 2018). Indeed, lysosomes and subsequently cell cytoplasm become overloaded with these aggregates, with associated oxidative stress, altered proteostasis, neuronal cytoskeletal and trafficking perturbations, and glial reactive transformation, potentially modifying risk of neurodegenerative disease (reviewed in Moreno-Garcia et al., 2018). Given that lipofuscin aggregate accumulation has been consistently noted in various aged animal (Maxwell et al., 2018) and indeed human motor neurons during normal ageing (Tomlinson and Irving, 1977; Rygiel et al., 2014), this phenomenon may thereby be relevant in ALS.

The dysfunction of motor neuron mitochondria with normal ageing (Rygiel et al., 2014) is intriguing, seeing that this mechanism has been noted as a key contributor to ALS pathology (reviewed in Van Damme et al., 2017). Lumbar spinal cord sections from 12 elderly patients revealed a subset of motor neurons with mitochondrial respiratory chain complex 1 deficiency, a phenotype not present in human foetal (911 weeks post-conception) spinal cords (Rygiel et al., 2014). Mitochondrial DNA copy number and cell body size were also reduced in complex 1 deficient motor neurons (Rygiel et al., 2014). With potential effects on neuronal function, viability and survival, it is possible that respiratory chain deficiency with normal ageing may instigate motor neuron dysfunction and degeneration (Rygiel et al., 2014) and this is consistent with such defects having an important role in age-related neurodegeneration and ALS, although this clearly requires further direct investigation to understand comprehensively.

Electrophysiological studies on aged wild-type mice showed alterations in motor neuron membrane and excitability properties (Moldovan et al., 2016). Indeed, ageing led to changes in voltage gated sodium channel expression, more specifically, ectopic expression of Nav1.8 on aged motor axons, affecting axonal membrane functionality (Moldovan et al., 2016). These electrophysiological alterations were attenuated with pharmacological blocking of Nav1.8, and in sensory neuron-specific Nav1.8 null mice (Moldovan et al., 2016). Altogether, although itself not neurotoxic, ectopic expression of Nav1.8 during ageing can leave motor neurons with higher energy requirements vulnerable to progression of neurodegeneration and neuronal pathology (Moldovan et al., 2016). Age-related membrane excitability alterations and changes potentially consistent with membrane depolarization were also noted in a non-invasive electrophysiological study of patient median motor axons (Bae et al., 2008). Age-associated electrical abnormalities may thereby leave aged motor neurons susceptible to further neuronal insult and neurodegenerative pathology.

A number of studies have identified key genes and pathways in normal motor neuron ageing, which can help better understand the potential intersect between ageing and disease. Indeed, transcriptomic analysis in Drosophila revealed matrix metalloproteinase 1 (dMMP1) to not only undergo an age-related increase in expression in motor neurons, but also cause motor functional defects that become more severe with further ageing when overexpressed in a subset of motor neurons (Azpurua et al., 2018). Impairment of presynaptic neurotransmitter release at the NMJ was the proposed mechanism (Azpurua et al., 2018). The upregulation of matrix metalloproteinases in ageing may be of special significance in age-related neurodegeneration and namely ALS, with TDP-43 overexpression in neurons accelerating the rate of dMMP1 accumulation (Azpurua et al., 2018) and suggesting a potential pathogenic mechanism linking ageing and ALS.

Mice with perturbed excision repair cross-complementation group 1 gene (Ercc1 / mice), deficient in a number of DNA repair system components including nucleotide excision repair and double strand break repair, gained an aberrant motor phenotype that progressively declined with ageing (de Waard et al., 2010). Alongside activation of CNS microglia and astrocytes, age-associated motor neurodegeneration and NMJ pathology, genotoxic stress, DNA damage and Golgi apparatus abnormalities were noted in Ercc1 / mice (de Waard et al., 2010). Hence, defective DNA repair mechanisms lead to motor neuron degeneration and functional decline in an age-dependent manner (de Waard et al., 2010). TDP-43 and fused in sarcoma (FUS) pathology did not develop in these motor neurons, suggesting DNA damage from ERCC1 deficiency is not sufficient to recapitulate ALS-related pathology (de Waard et al., 2010). Nonetheless, DNA damage accumulation with normal ageing can prove a vital risk factor contributing to neurodegenerative disease and ALS (de Waard et al., 2010).

Despite not causing motor functional decline, transgenic expression of mutant heat shock protein beta 1 (HSPB1), associated with motor neuropathies, showed age-dependent subclinical motor axonal pathology, characterized by electrophysiological changes and neuropathological hallmarks (Srivastava et al., 2012). Conditional knockout of dynactin P150Glued in murine neurons not only led to age-dependent motor functional decline but also caused preferential degeneration of spinal motor neurons in aged animals (Yu et al., 2018). Many deleterious phenotypes only present when the animals in these studies age, which raises the hypothesis that normal ageing might be a prerequisite for motor neuronal degeneration in ALS. It is possible that the ageing of motor neurons, in addition to causing direct cellular phenotypes, might render the system vulnerable to subsequent ALS disease-specific mechanisms, although further studies are required to definitively resolve this.

With evidence suggesting that normal ageing affects motor neuron number, structure and functional capacity, it is unsurprising that age-related effects may play a vital role in neurodegenerative diseases involving motor neurons, such as ALS. An integration of ageing and ALS research can allow for better mechanistic insight and therapeutic advancement, ultimately leading to patient benefit.

The nervous system and skeletal muscle are intimately linked, with motor neuron-derived electrical stimulation ultimately allowing muscle contraction and, in turn, movement. As the postsynaptic constituent of the NMJ, muscle itself has been implicated as an early component in ALS pathogenesis, with muscle weakness an initial and debilitating clinical symptom (reviewed in Hobson and McDermott, 2016). Indeed, skeletal muscle-specific expression of mutant (G93A/G37R) and wild-type human SOD1 in transgenic mice disrupted NMJs and led to motor neuron degeneration and a corresponding functional phenotype (Wong and Martin, 2010). Mitochondrial dysfunction, namely alterations in morphology and distribution, and the induction of protein kinase C have been implicated as key mechanisms destabilizing NMJs in transgenic mice with muscle restricted SOD1G93A (Dobrowolny et al., 2018). As well as its implications in ALS, skeletal muscle undergoes a variety of structural and functional changes in normal ageing, which may also link to its roles in disease. Sarcopenia, the highly prevalent, age-associated decline in skeletal muscle mass, force and function, not only significantly impacts patient quality of life, but also bears key connotations for the healthcare system owing to its links with frailty (Clegg et al., 2013), falls, disability and mortality (reviewed in Marzetti et al., 2017). The clinical phenotype of sarcopenia is underpinned by the effects of ageing on skeletal muscle and its environment (reviewed in Marzetti et al., 2017), which we discuss below.

Skeletal muscle adult stem cells (satellite cells) reside between muscle fibre sarcolemma and basement membrane in a quiescent state, but, on injury, have the capacity to asymmetrically divide to both self-replicate and form progeny which ultimately differentiate to new muscle fibres (Morgan and Partridge, 2003). With ageing, satellite cells lose their capacity to regenerate damaged muscle (Sousa-Victor et al., 2014b), with cell intrinsic alterations implicated.

Indeed, induction of P16INK4a in geriatric mice, a regulator of cellular senescence, drove satellite cells to a pre-senescent phenotype, which was further advanced to irreversible full senescence when the cells were placed under proliferative pressure (Sousa-Victor et al., 2014b). Functionally, the cells showed defects in activation, ability to proliferate and capacity to self-renew, altogether preventing successful muscle fibre regeneration (Sousa-Victor et al., 2014b). Adult (56 months) and old (2024 months) murine satellite cells actively repress P16INK4a to maintain a state of reversible quiescence, which underpins their regenerative function. Geriatric (2832 months) animals had P16INK4a repression lifted, and underwent the abovementioned state change (reversible quiescence irreversible pre-senescence geroconversion to full senescence). Knocking out Bmi1, a component of the main repressor of the INK4a locus, induced a senescent-like phenotype in young satellite cells with resultant functional defects (Sousa-Victor et al., 2014a). Interestingly, from a therapeutic perspective, inhibition of P16INK4a in geriatric and progeric mouse models was sufficient to reverse the senescent phenotype and restore regeneration (Sousa-Victor et al., 2014a). Thereby, with aged satellite cells unable to facilitate skeletal muscle recovery following insult, it may be left more vulnerable to further disease-specific pathology in ALS.

Protein arginine methyltransferase 7 (PRMT7) knockout mice showed reduced skeletal muscle mass and increased fat at 8 months of age, with delayed differentiation and premature senescence as putative underlying mechanisms. Increased p21 (senescence marker) and reduced DNMT3b were noted, with restoration of the latter rescuing the senescent phenotype in vitro. Although regenerative capacity was similar between young wild-type and Prmt7 / mice 21 days following tibialis anterior cardiotoxin injury, the knockouts showed significant structural regenerative aberrance with age (8 months) when compared to Prmt7 / uninjured and wild-type injured/uninjured mice. Indeed, satellite cell number, self-renewal ability and regenerative function were defective (Blanc et al., 2016). Mice heterozygous for Ku80 (Xrcc5), a facilitator of genomic and telomere stability, showed a muscle phenotype resembling accelerated physiological ageing. Following recurrent injury, heterozygous mice (and Ku80 null mice) showed fewer self-renewing stem cells, with a corresponding increase in committed and expanding cells. Injuring the tibialis anterior muscle of adult Ku80 wild-type, heterozygous and null mice twice (15-day interval) resulted in decreased regeneration in the 18-month compared to the 2-month wild-type, as well as reduced capacity to regenerate in Ku80 heterozygous and null mice (as measured 7 days after second injury) (Didier et al., 2012). The heterozygous stem cells were also shown to have significantly shorter telomeres than wild-type mice as well as features of skeletal muscle premature ageing (Didier et al., 2012). Satellite cells also lose functional heterogeneity with age, whilst maintaining the clonal complexity of their youthful counterparts, as visualized using in vivo multicolour lineage tracing (Tierney et al., 2018). Aged satellite cells obtained via muscle biopsy of sedentary elderly patients showed deficits in antioxidant activity, cell membrane fluidity and intracellular basal calcium content compared to those from newborn or sedentary young patients (Fulle et al., 2005). Indeed, other intrinsic age-related satellite cell alterations might include DNA damage and mitochondrial abnormalities (reviewed in Brack and Munoz-Canoves, 2016), resembling molecular mechanisms in ALS (reviewed in Van Damme et al., 2017).

Altogether, satellite cells develop a number of cell intrinsic changes with ageing, ultimately leading to their dysfunction and a homeostatically aberrant skeletal muscle system that is vulnerable to disease-specific insult. Moreover, ALS satellite cells have been shown to lose their differentiation potential (and consequently their regenerative capacity) compared to controls (Scaramozza et al., 2014), indicating shared phenotypic features between aged and ALS satellite cells.

As well as the abovementioned intrinsic satellite cell alterations, the niche in which these cells reside also undergoes age-associated changes. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), for example, is activated during ageing (Zhang et al., 2017). Specifically increasing NF-B signalling in satellite cells led to impaired repair following cryoinjury, a phenotype that was rescued by administration of an NF-B inhibitor (Oh et al., 2016). Isolation of satellite cells prior to injury indicated no intrinsic differences in proliferation or initiation of myogenesis. The presence of their differentiated muscle progeny with increased NF-B signalling seemed to negatively impact the stem cells and indeed blocking NF-B specifically in aged muscle fibres improved satellite cell function (Oh et al., 2016). Hence, age-associated non-cell autonomous impacts on satellite cells may also contribute to muscle aberrance in normal ageing and disease.

Muscle-specific inactivation of NF-B failed to ameliorate loss of muscle mass and neuromuscular function in aged muscle-specific inhibition of NF-B through expression of IB super repressor (MISR) mice (Zhang et al., 2017). Moreover, NF-B inhibition altered the expression of genes associated with muscle growth and NMJ function and caused accelerated early differentiation in vitro (Zhang et al., 2017). This highlights the key role of tightly regulating NF-B in order to prevent muscle aberrance with ageing. Indeed, NF-B alterations in various cell types are also implicated in the pathogenesis of ALS (Frakes et al., 2014).

A number of extrinsic signalling pathways (Wnt, TGF, Notch, FGF) have been noted to interact closely with ageing satellite cells, with key implications for the regenerative capacity of these cells (Chakkalakal and Brack, 2012). Indeed, Notch activity drops whereas TGF and pSmad3 increase in old muscle, inducing a loss of regenerative capacity (as confirmed by three different Smad3-targeted small hairpin RNAs restoring markers to youthful levels in satellite cells and enhancing myogenesis in old muscle) (Carlson et al., 2008). Evidence for the impact of the muscle niche also comes from studies of heterochronic parabiosis, which unite the circulatory systems of aged and young animals, with elderly tissues exposed to youth serum systemic factors. By separating young and aged contributions in vivo via GFP reporter labelling, notably, the native aged satellite cells were reactivated and enhanced myogenesis occurred post-injury (Conboy et al., 2005). Delta upregulation, indicative of Notch activity, was restored with exposure to young serum (Conboy et al., 2005). Growth differentiation factor 11 (GDF11) has been implicated as a key circulating rejuvenating factor, restoring structural and even functional deficits in aged mice (Sinha et al., 2014). Muscle transplantation between old and young rats revealed that old to young transplants had greater mass, maximum force and resembled young-young autografts histologically (Carlson and Faulkner, 1989), adding yet more support to the key role of the muscle niche in ageing. A less permissive and poorly sustainable aged muscle environment might prove vulnerable to disease-specific mechanisms, such as those in ALS.

Muscle mitochondrial function decreases with ageing, with wild-type mice showing decreased oxygen consumption rates and increased production of reactive oxygen species (ROS) as they age (Valentine et al., 2018). Autophagy, the lysosome-mediated process by which various cytosolic components are degraded, was diminished in muscle obtained from elderly sedentary patients, and muscle-specific knockout of autophagy-associated ATG7 in mice enhanced muscle atrophy, inflammation, abnormal structure and reduced life expectancy in this model (Carnio et al., 2014). Inhibition of autophagy also increased mitochondria frequency, size and structural aberrance, leading to oxidative stress and ROS, which in turn disturbs interaction between actin and myosin and force generation (Carnio et al., 2014). Old (29 months) male rats showed a maladaptive endoplasmic reticulum (ER) stress response on hindlimb reloading following 14 days of unloading (which had caused disuse-induced atrophy and deficits in force generation) (Baehr et al., 2016). Hence, ER and oxidative stress, mitochondrial dysfunction and autophagy also play key roles in muscle ageing, and indeed, all of these pathways are also implicated in ALS pathogenesis (reviewed in Loeffler et al., 2016; Van Damme et al., 2017).

With the abovementioned mechanisms of normal muscle ageing sharing associations with the pathophysiology of sarcopenia, it is important to consider the role of age-related skeletal muscle perturbations in other diseases such as ALS. With muscle intimately structurally and functionally linked with lower motor neurons, it is possible that defective aged skeletal muscle fails to fulfil its role in the complex relationship, thereby contributing to disease. Indeed, it is at the level of the NMJ where skeletal muscle ageing may play its largest role in ALS. Skeletal muscle expressed FGFBP1, found to be a key protective factor to preserve NMJ integrity, was reduced in both normal ageing and ALS (SOD1G93A mice) (Taetzsch et al., 2017), suggesting a common pathological mechanism between the two. Hence, neuromuscular structural and functional consequences result from the effects of ageing at the level of the skeletal muscle, with potential mechanistic overlaps with ALS.

With non-neuronal cells matching neuronal numbers in the human brain (Azevedo et al., 2009), astrocytes, the most abundant of the CNS glial cells, perform an array of functions fundamental in development and adulthood including synaptogenesis and synaptic elimination, neurotransmitter recycling, bloodbrain barrier maintenance and supporting neuronal survival (reviewed in Vasile et al., 2017). With a non-cell autonomous contribution to neurodegenerative disease pathogenesis now widely accepted over the traditional 'neuron centric' model, astrocytes have emerged as vital disease players in ALS, with both toxic gain-of-function (Nagai et al., 2007) and loss of neuronal support implicated (Das and Svendsen, 2015; Tyzack et al., 2017). Interestingly, there were a number of similarities between 150 day end-stage SOD1 overexpressing astrocytes and 300 day wild-type aged astrocytes with analysis of growth rates, molecular profiles, markers of senescence and motor neuron survival revealing parallels between ALS and aged wild-type samples (Das and Svendsen, 2015). This indicated that the SOD1 mutant ALS astrocytes were displaying the effects of normal ageing at an accelerated rate (Das and Svendsen, 2015). Indeed, astrocytes undergo significant age-associated alterations, which affect their ability to interact with surrounding cells and consequently their vital functions in the CNS. If astrocytes in ALS are a pathologically hastened form of their normally aged counterparts, a true understanding of astrocyte ageing will provide insight into not only the mechanisms behind age-related neurological decline, but also ALS. This is discussed below.

Astrocytes reacting to injury segregate into two groups dependent on mechanisms of injury, as revealed by transcriptomic analysis (Zamanian et al., 2012). Astrocytes subjected to inflammatory stimuli such as lipopolysaccharide (LPS) adopt an A1 phenotype, and those exposed to ischaemia develop an A2 phenotype, with the former upregulating genes involved in synaptic elimination (e.g. complement cascade), and the latter upregulating neurotrophic, reparative and survival promoting genes (e.g. thrombospondins) (reviewed in Liddelow and Barres, 2017).

Astrocytes in ALS and a number of other neurodegenerative diseases possess an A1 reactive phenotype (Clarke et al., 2018). Aged (2 years) mouse astrocytes from an array of brain regions upregulated more A1 reactive genes (including the complement factor C3) than A2 reactive genes, indicating that normal ageing is associated with the more deleterious A1 astrocytic phenotype (Clarke et al., 2018). Indeed, promotion of complement regulated synaptic elimination by normally aged A1 astrocytes may make the brain more vulnerable to neurodegenerative diseases (Clarke et al., 2018).

Alterations in astrocytes with age render them more susceptible to insult. Pure oxidative stress via hydrogen peroxide exposure and mixed stressors (including oxidative stress) in glucose with or without oxygen deprivation affected primary mouse astrocytes matured in vitro more than their young counterparts, indicating disruption in the balance between synthesis and scavenging of reactive oxygen species in older astrocytes (Papadopoulos et al., 1998). Indeed, three key antioxidant species, namely glutathione, catalase and SOD were maintained or even elevated in older astroglia, suggesting alternative mechanisms behind the greater injury in these cells (Papadopoulos et al., 1998). Iron, which catalyses free radical synthesis, was increased in aged astrocytes (Papadopoulos et al., 1998). The enhanced vulnerability of aged astrocytes to oxidative stress may play a key role in disease, with oxidative stress playing an important role in ALS pathogenesis (reviewed in Barber and Shaw, 2010).

In turn, primary astrocyte cultures subjected to oxidative stress (hydrogen peroxide) develop a senescent phenotype, also achieved by other stressors (proteasome inhibition via lactacystin-2 and extensive cellular replication) (Bitto et al., 2010). Stressed cells acquired characteristic morphological features of senescence, cell cycle arrest and expressed senescence-associated markers including -galactosidase, p16, p21 and p53 (Bitto et al., 2010). Replicative senescence was also seen, with associated reductions in telomere length and G1 cell cycle arrest (Bitto et al., 2010). Given the abovementioned susceptibility of astrocytes to oxidative and other stress (Papadopoulos et al., 1998; Bitto et al., 2010) in normal ageing, the development of their senescent phenotype may carry a range of functional defects which ultimately lead to their failure to support themselves and neurons in ageing and disease. Transcriptomic analysis of multiple regions within aged murine brains and subsequent pathway analysis revealed that cholesterol synthesis was downregulated in aged astrocytes (Boisvert et al., 2018). With cholesterol a key constituent of presynaptic vesicle synthesis, neuronal synaptic function could become perturbed as a result of astrocytic ageing (Boisvert et al., 2018). Genes from immune pathways including antigen presentation and the complement cascade, were upregulated, indicating a propensity towards cellular stress and synaptic elimination in aged astrocytes (Boisvert et al., 2018). Transcriptomic analysis also uncovered stark regional heterogeneity in astrocyte expression profiles both within the murine cortex (Boisvert et al., 2018) and between different human post-mortem brain regions (Soreq et al., 2017). In human brains, the most pronounced age-related shifts in astrocyte region-specific genes were identified in the hippocampus and substantia nigra, major sites of pathology in the two most common age-associated neurodegenerative diseases (Alzheimer's disease and Parkinson's disease, respectively) (Soreq et al., 2017). The ageing of astrocytes rather than neurons, which show significantly fewer region-specific gene expression changes with age, may therefore underpin regional vulnerability and sites of pathological involvement in neurodegenerative diseases (Soreq et al., 2017). This finding potentially bears significance for ALS, where there is regional and subtype specific vulnerability (reviewed in Nijssen et al., 2017).

Astrocytes possess the key quality of forming intimate interactions with other glial cells in brain physiology. Their interaction with microglia, the immune cells of the CNS, affects microglial branching and distribution (Lana et al., 2019). In ageing, this direct interaction is impaired, with microglial morphology, distribution and ability to efficiently phagocytose disrupted (Lana et al., 2019). The latter could lead to accumulation of toxic proinflammatory cell debris in the CNS (Lana et al., 2019). Key astrocytic interactions with cells in their local environment thereby become perturbed upon ageing, leading to disruption of other cell types in their vicinity via non-cell autonomous mechanisms.

With their sheer number and multiple functional roles, it is unsurprising that astrocytes are heavily relied upon by the human nervous system. Their disruption with normal ageing can therefore have vital knock-on effects on other surrounding cells, such as neurons and microglia, overall leading to a CNS more vulnerable to age-related pathology and neurodegenerative disease.

Schwann cells adopt various phenotypes dependent on extrinsic cues. Originating from neural crest, immature Schwann cells can either differentiate into non-myelinating or myelinating Schwann cells, the latter via a promyelin Schwann cell intermediate (reviewed in Jessen et al., 2015; Santosa et al., 2018). Indeed, at the NMJ, the peri-synaptic or terminal Schwann cell (TSC) falls within the non-myelinating category and has been implicated in neuromuscular diseases including ALS (reviewed in Santosa et al., 2018). TSCs have been shown to undergo morphological changes in ALS patients, including developing vast cytoplasmic processes (Bruneteau et al., 2015). Moreover, TSCs, which normally juxtapose the NMJ (Figure 2), are sometimes found to invade the NMJ itself, occupying the space between the presynaptic motor axon terminal and the postsynaptic membrane (termed the synaptic cleft), in turn reducing the surface area for neuromuscular transmission (Bruneteau et al., 2015). Morphological alterations have also been reported in a SOD1G93A mutant model of ALS, with these changes preceding motor terminal degeneration and denervation (Carrasco et al., 2016b). More specifically, it was found that TSCs were lost from NMJs with pre-terminal Schwann cell processes taking their place (Carrasco et al., 2016b). Additionally, an absence of immunostaining for P75 (post-denervation marker) and S100 (a Schwann cell marker) following experimental denervation suggests that both TSCs and pre-terminal Schwann cells are lost in SOD1G93A mutant mice, hence unable to facilitate reinnervation following denervation (such as in ALS) (Carrasco et al., 2016a). Given the vital role of TSCs in maintaining NMJ health and function, and their significance in disease, understanding the impact of ageing on this cell type is essential to truly appreciating their role in ALS pathogenesis. We discuss ageing phenotypes in Schwann cells before subsequently focusing on TSCs.

Neurons of the peripheral nervous system have a remarkable capacity to regenerate, especially when compared to their central counterparts. Integral to this process are Schwann cells, which whether myelinating or non-myelinating, adopt a repair phenotype post nerve injury, regulated by the transcription factor c-Jun (reviewed in Jessen et al., 2015). Regeneration tracks laid by these cells form scaffolds that facilitate axonal reinnervation of their intended targets (reviewed in Jessen et al., 2015). Ageing in Schwann cells is associated with a decline in regenerative capacity (Painter et al., 2014). Indeed, when compared to young mice at 2 months of age, elderly 24-month-old mice had delayed initiation and slower sensory and motor functional recovery, with 12-month-old mice possessing an intermediate capacity (Painter et al., 2014). Furthermore, aged animals receiving young nerve grafts equalled young functional recovery and young animals receiving aged nerve grafts developed a delay in functional restoration (Painter et al., 2014). Genetic analysis revealed that aged animals had downregulated repair function genes, with age-associated decline in growth factor and mitosis genes, and had failed to suppress a myelinating phenotype after injury when compared to their young counterparts (Painter et al., 2014). In aged animals 1 day post nerve injury, c-Jun, the abovementioned regulator of the Schwann cell repair phenotype, only managed one-fifth of the levels achieved in young animals, in line with aged Schwann cell aberrance in dedifferentiation and subsequent failure in functional regeneration (Painter et al., 2014). With ageing impairing Schwann cell facilitated regeneration, neurons may fail to combat damage experienced in both normal ageing and ALS, leading to an enhanced deleterious phenotype.

Dedifferentiated Schwann cells play a role in luring macrophages to the site of axonal damage after injury (Painter et al., 2014). This function too was disrupted in aged animals, with a delay in macrophage recruitment (Painter et al., 2014). Age-related immune dysfunction was also implicated when grafting sections of rat sciatic nerves from 2- to 18-month-old (young-aged) rats and vice versa (aged-young) with young-young and aged-aged graft controls. Both Schwann cells and macrophages play key roles in debris clearance via phagocytosis after injury (Scheib and Hoke, 2016). Indeed, there was more debris in aged-aged controls compared to young-young grafted animals, with young-aged and aged-young grafts displaying intermediate levels. Hence, as cells involved in debris clearance (Schwann cells and immune macrophages) age, their phagocytotic capacity diminishes, a finding replicated in vitro for both cell types (Scheib and Hoke, 2016).

It has been long noted that Schwann cell ultrastructural abnormalities accompany ageing in rat peripheral nerves (Thomas et al., 1980). Schwann cells in aged rats developed a phenotype with extended attenuated processes projecting from adaxonal Schwann cell into the axon, in turn compartmentalizing the axon length into small sections, appearing 'honeycombed' (Thomas et al., 1980). Intracytoplasmic inclusions were also noted (Thomas et al., 1980). The presence of disproportionately thin myelin sheaths around some axons also indicated remyelination to be present (Thomas et al., 1980). A reduced myelin diameter was also noted in aged C57BL/6 mice, alongside alterations to essential myelin-related proteins including increased carbonylation and reduced protein expression of PMP22 in sciatic nerves (Hamilton et al., 2016). We speculate that structurally aberrant aged Schwann cells may not be able to function optimally and support neurons, which then may potentially allow disease mechanisms, such as those in ALS, to thrive in an already vulnerable environment.

TSCs in aged wild-type mice showed numerical decline, with a progressively lower proportion of NMJs possessing TSCs between 14 and 33 months of age (100% NMJs had TSCs at 9 months of age) (Snyder-Warwick et al., 2018). This loss was accompanied by structural changes in the remaining TSCs, which displayed thinner processes and irregular TSC bodies with heterogeneous S100 staining (Snyder-Warwick et al., 2018). Brain-specific overexpression of SIRT1, implicated in mammalian ageing, enhanced the number of TSC processes and bodies compared to age-matched controls, with a higher proportion of NMJs possessing TSCs in, altogether, a more youthful phenotype (Snyder-Warwick et al., 2018). Additionally, the knockdown of SIRT1 specific to the dorsomedial hypothalamus led to excessively large TSC bodies that frequently resided outside the NMJ, as well as fewer TSCs per NMJ (Snyder-Warwick et al., 2018). Although aberrance was not identical in knockdown and aged wild-type animals, both showed increased frequency of TSC abnormalities, with the knockdown potentially a 'more aged' phenotype (Snyder-Warwick et al., 2018). Their imperative roles in sustaining optimal NMJ function implicate TSCs as being a highly relevant cellular candidate linking ageing and ALS.

Read more here:
Decoding the Relationship Between Ageing and ALS - Medscape

Fate Therapeutics Inc (NASDAQ:FATE) Gets FDA Approval On IND Application Of iPSC-based CAR T-Cell Therapy – BP Journal

Fate Therapeutics Inc (NASDAQ:FATE) recently announced that it received the FDAs green light for an iPSC-based CAR T-Cell therapy that the company calls FT819.

Fate Therapeutics has been developing FT819 as a chimeric antigen receptor (CAR) that is engineered to combat CD19+ malignancies. It is the first CAR T-cell therapy that is made using clonal master induced pluripotent stem cell (iPSC). This technology allows the drug to be fitted with features that allow it to have better safety and efficacy profile.

The approval of FT819s Investigational New Drug (IND) represents an important milestone for the company and for patients suffering from various types of cancer. The CAR T-cell therapy will be used for various indications, including non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL). In other words, it will be used to target relapsed B-cell malignancies.

The clearance of our IND application for FT819 is a ground-breaking milestone in the field of cell-based cancer immunotherapy, stated Fate Therapeutics CEO Scott Wolchko.

The CEO also noted that his companys ability to make CAR T cells from an iPSC line that has been master engineered prevents more patients from accessing treatment in a timely manner. It also provides patients with therapies that have more curative potential. Wolchko also pointed out that the current level of progress that Fate Therapeutics has achieved with CAR T-cell therapy is courtesy of the partnership that the company struck with Memorial Sloan Kettering four years ago.

Fate Therapeutics made FT819 address some of the shortcomings of the currently available CAR T-cell therapies derived from donors and patients. The company also announced recently that it signed an exclusive license deal with Baylor College of Medicine. The deal is aimed at developing iPSC-derived therapies that are rejection-resistant.

Wolchko pointed out that strategies that allow allogeneic cells to overcome immune rejection while facilitating normal functions of the hematopoietic system have been gaining a lot of traction and interest lately. He also added that preclinical data has already demonstrated that the ability to allogeneic cell therapies can deliver significant efficiencies.

Original post:
Fate Therapeutics Inc (NASDAQ:FATE) Gets FDA Approval On IND Application Of iPSC-based CAR T-Cell Therapy - BP Journal

A functional genomics approach to investigate the differentiation of iPSCs into lung epithelium at air-liquid interface. – Physician’s Weekly

The availability of robust protocols to differentiate induced pluripotent stem cells (iPSCs) into many human cell lineages has transformed research into the origins of human disease. The efficacy of differentiating iPSCs into specific cellular models is influenced by many factors including both intrinsic and extrinsic features. Among the most challenging models is the generation of human bronchial epithelium at air-liquid interface (HBE-ALI), which is the gold standard for many studies of respiratory diseases including cystic fibrosis. Here, we perform open chromatin mapping by ATAC-seq and transcriptomics by RNA-seq in parallel, to define the functional genomics of key stages of the iPSC to HBE-ALI differentiation. Within open chromatin peaks, the overrepresented motifs include the architectural protein CTCF at all stages, while motifs for the FOXA pioneer and GATA factor families are seen more often at early stages, and those regulating key airway epithelial functions, such as EHF, are limited to later stages. The RNA-seq data illustrate dynamic pathways during the iPSC to HBE-ALI differentiation, and also the marked functional divergence of different iPSC lines at the ALI stages of differentiation. Moreover, a comparison of iPSC-derived and lung donor-derived HBE-ALI cultures reveals substantial differences between these models. 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

PubMed

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A functional genomics approach to investigate the differentiation of iPSCs into lung epithelium at air-liquid interface. - Physician's Weekly

Global Induced Pluripotent Stem Cells (iPSCs) Market Evenly Poised To Reach A Market Value of USD 2610.10 million By Share, Size and Leading Players…

Few of the major competitors currently working in global induced pluripotent stem cells market areFUJIFILM Holdings Corporation, Astellas Pharma Inc, Fate Therapeutics, Bristol-Myers Squibb Company, ViaCyte, Inc., CELGENE CORPORATION, Vericel Corporation, KCI Licensing, Inc, STEMCELL Technologies Inc., Japan Tissue Engineering Co., Ltd., Organogenesis Holdings Inc, Lonza, Takara Bio Inc., Horizon Discovery Group plc, Thermo Fisher Scientific.

How does this market Insights help?

Key Developments in the Market:

In March 2018, Kaneka Corporation announced that they have acquired a patent in the Japan for the creation of the method to mass-culture pluripotent stem cells including iPS cells and ES cells. This will help the company to use the technology to produce high quality pluripotent stem cells which can be used in the drug and cell therapy.

In March 2015, Fujifilm announced that they have acquired Cellular Dynamics International. The main aim of the acquisition is to expand their business in the iPS cell-based drug discovery support service with the use of CDS technology. It will help them to product high- quality automatic human cells with the help of the induced pluripotent stem cells. This will help the company to be more competitive in the drug discovery and regenerative medicine.

Key questions answered in the Global Induced Pluripotent Stem Cells (iPSCs) Market report include:

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Breakdown Of Global Induced Pluripotent Stem Cells (iPSCs) Market

By Cell Type

Hepatocytes

Fibroblasts

Keratinocytes

Amniotic Cells

Neurons

Others

By Application

Drug Development

Regenerative Medicine

Toxicity Testing

Academic Research

By End-User

Academic and Research Institutes

Biotechnology Companies

Others

By Geography

North America

South America

Europe

Asia-Pacific

Middle East & Africa

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Global Induced Pluripotent Stem Cells (iPSCs) Market Evenly Poised To Reach A Market Value of USD 2610.10 million By Share, Size and Leading Players...

Fate Therapeutics Receives FDA Clearance of IND for FT819 in B-Cell Malignancies – OncLive

The FDA has cleared an investigational new drug application (IND) for the first-of-its-kind, off-the-shelf CAR T-cell product FT819, which targets CD19-positive malignancies, according to an announcement from Fate Therapeutics, the drugs co-developer.1

The biopharmaceutical company plans to evaluate the product as a treatment for patients with relapsed/refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL).

"The clearance of our IND application for FT819 is a ground-breaking milestone in the field of cell-based cancer immunotherapy. Our unique ability to produce CAR T cells from a clonal master engineered iPSC line creates a pathway for more patients to gain timely access to therapies with curative potential, Scott Wolchko, president and chief executive officer of Fate Therapeutics, stated in a recent press release.

As the first CAR-T cell therapy created from cell clonal master-induced pluripotent stem cell (iPSC) line, FT819 can be mass-produced and delivered off the shelf to offer broader access to the treatment. This CAR T-cell product was also developed to improve the safety and efficacy of this modality, and address limitations linked with the patient- and donor-derived products that are currently available, according to Fate Therapeutics.

The treatment is the result of a collaborative effort between a group of investigators led by Michael Sadelain, MD, PhD, the director of the Center for Cell Engineering and head of Gene Expression and Gene Transfer Laboratory at from Memorial Sloan Kettering Cancer Center and Fate Therapeutics.

Four years ago, we first set out under our partnership with Memorial Sloan Kettering led by Dr. Michel Sadelain to improve on the revolutionary success of patient-derived CAR T-cell therapy and bring an off-the-shelf paradigm to patients, and we are very excited to advance FT819 into clinical development, Wolchko added.

In the development of the product, investigators incorporated 1XX CAR signaling domain in an effort to extend T-cell effector function without inducing exhaustion. Additionally, CAR transgene was inserted directly into the T-cell receptor alpha constant (TRAC) locus, which is believed to encourage uniform CAR expression and amplify T-cell potency. Notably, the therapy was also designed to result in the complete bi-allelic disruption of T-cell receptor expression to prevent graft-versus-host disease (GVHD), a notable complication that is known to occur with allogeneic T-cell therapy.

Preclinical data presented during the 2020 AACR Virtual Meeting II showed that FT819 possessed a uniform product profile of 95% CAR+, TCR-, CD45+, CD7+, and CD3+ with most of the CD8 T cells expressing CD8.2 The global gene expression profile of the product showcased high similarity to primary CD19-targeted CAR T cells, thus solidifying its identity as a T lymphocyte, according to the study authors.

Functional assessment revealed strong antigen-specific cytolytic activity against leukemia and lymphoma cell lines (P = .0004) with the product. On-target, off-tumor cytolysis of CD19-positive B cells were confirmed in mixed lymphocyte reaction assay. Moreover, FT819 proved to be unable to produce a GVH response in a co-culture assay with anti-TCR crosslinking antibodies. Furthermore, FT819 was shown to control tumor growth (P = .0003 at day 21) in disseminated leukemia xenograft mouse studies. The product also showed sustained bone marrow localization for 45 days following treatment in a systemic administered leukemia model.

Collectively, these studies demonstrate that FT819 is a potent, homogenous CAR19 T-cell product candidate and can be potentially effectively used off-the-shelf in the treatment of B-cell malignancies, the investigators concluded.

In a planned multicenter phase 1 trial, investigators will identify the maximum-tolerated dose of FT819, as well as the clinical activity and safety of the product in 297 patients with B-cell malignancies, including CLL, ALL, and NHL. Notably, each indication will enroll independently and 3 doses of FT819 will be examined: a single dose of the product (regimen A), a single dose of FT819 in combination with IL-2 cytokine support (regimen 2), and 3 fractionated doses of FT819 (regimen C). Dose-expansion cohorts comprised of up to 15 patients for each indication and regimen can be used to further examine the clinical activity of the CAR T-cell product.

Originally posted here:
Fate Therapeutics Receives FDA Clearance of IND for FT819 in B-Cell Malignancies - OncLive

Global Induced Pluripotent Stem Cells Market 2020 Segmentation Trend, CAGR Status, Growth, Analysis and Forecast to 2026 – Cole of Duty

Induced Pluripotent Stem Cells Market Production by Regions:

The analyzed data on the Induced Pluripotent Stem Cells market help you put up a brand within the industry while competing with the giants. This report provides insights into a dynamic competitive environment. It also offers a progressive viewpoint on different factors driving or restricting market growth.

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Detailed TOC of Global Induced Pluripotent Stem Cells Market Trends, Status and Forecast 2020-2026

1 Induced Pluripotent Stem Cells Market Overview

1.1 Product Overview and Scope of Induced Pluripotent Stem Cells

1.2 Covid-19 Impact on Induced Pluripotent Stem Cells Market Production Growth Rate Segment by Type

1.3 Covid-19 Impact on Induced Pluripotent Stem Cells Segment by Application

1.4 Covid-19 Impact on Global Induced Pluripotent Stem Cells Market Size Estimates and Forecast by Region

1.5 Covid-19 Impact on Global Induced Pluripotent Stem Cells Market Growth Prospects

1.5.1 Global Induced Pluripotent Stem Cells Revenue Estimates and Forecasts (2015-2026)

1.5.2 Global Induced Pluripotent Stem Cells Production Capacity Estimates and Forecasts (2015-2026)

1.5.3 Global Induced Pluripotent Stem Cells Production Estimates and Forecasts (2015-2026)

1.6 Coronavirus Disease 2019 (Covid-19) Impact Will Have a Severe Impact on Global Growth

1.6.1 Covid-19 Impact: Global GDP Growth, 2019, 2020 and 2021 Projections

1.6.2 Covid-19 Impact: Commodity Prices Indices

1.6.3 Covid-19 Impact: Global Major Government Policy

1.7 The Covid-19 Impact on Induced Pluripotent Stem Cells Industry

1.8 COVID-19 Impact: Induced Pluripotent Stem Cells Market Trends

2 Covid-19 Impact on Market Competition by Manufacturers

2.1 Global Induced Pluripotent Stem Cells Market Share by Manufacturers (2015-2020)

2.2 Global Induced Pluripotent Stem Cells Revenue Share by Manufacturers (2015-2020)

2.3 Market Share by Company Type (Tier 1, Tier 2 and Tier 3)

2.4 Global Induced Pluripotent Stem Cells Average Price by Manufacturers (2015-2020)

2.5 Manufacturers Induced Pluripotent Stem Cells Production Sites, Area Served, Product Types

2.6 Induced Pluripotent Stem Cells Market Competitive Situation and Trends

2.6.1 Induced Pluripotent Stem Cells Market Concentration Rate

2.6.2 Global Top 3 and Top 5 Players Market Share by Revenue

2.6.3 Mergers & Acquisitions, Expansion

3 Covid-19 Impact on Production and Capacity by Region

3.1 Global Induced Pluripotent Stem Cells Market Share by Regions (2015-2020)

3.2 Global Induced Pluripotent Stem Cells Revenue Market Share by Regions (2015-2020)

3.3 Global Induced Pluripotent Stem Cells Production Capacity, Revenue, Price and Gross Margin (2015-2020)

3.4 North America Induced Pluripotent Stem Cells Production

3.4.1 North America Induced Pluripotent Stem Cells Production Growth Rate (2015-2020)

3.4.2 North America Induced Pluripotent Stem Cells Production Capacity, Revenue, Price and Gross Margin (2015-2020)

3.5 Europe Induced Pluripotent Stem Cells Production

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Global Induced Pluripotent Stem Cells Market 2020 Segmentation Trend, CAGR Status, Growth, Analysis and Forecast to 2026 - Cole of Duty

Hybrid products could drive first wave of cell-based meat launches, predicts Higher Steaks as it unveils pork belly, bacon prototypes -…

By weight, the pork belly prototypes contain 50% muscle cells grown in a bioreactor (without the use of bovine serum) and 50% plant-based proteins and fats; while the bacon contains 70% muscle cells and 30% plant-based materials.

Were already seeing hybrid burgers and nuggets [combining conventional and plant-based meat from US meat giants such as Tyson Foods and Perdue Farms], and I absolutely think youll see this with cell-based meat as well, said co-founder and CEO Benjamina Bollag, who was speaking to FoodNavigator-USA shortly afterbiotech research lab 3D Bioprinting Solutions unveileda collaboration with KFC to bring hybrid nuggets containing 80% plant-based materials to the Russian market.

Combining cell-based meat - which will likely enter the market in small quantities at a premium price - with plant proteins and fats, could help startups enter the market with more affordable products and ease consumers into the concept, she said, although Higher Steaks longer-term ambition is to make 100% cell-based products cost competitive.

Higher Steaks is using induced pluripotent stem cells (iPS), which behave like embryonic stem cells in that they can replicate/proliferate extensively (without having to keep going back to the original source) and differentiate into multiple cells types such as muscle and fat, said Bollag,a chemical engineer who co-foundedHigher Steaksin 2017 with stem cell scientist Dr. Stephanie Wallis and Prof. David Hay, chair of tissue engineering at the Center for Regenerative Medicine at the University of Edinburgh.

Stem cell scientist Dr Ruth Faram has since joined as head of R&D, while Dr James Clark, formerly CTO at Predict Immune, recently joined as chief science officer to help the startup scale up its technology, she added.

Right now, the team is still exploring whether it makes most sense to grow these cell types separately and combine them at the end to make products, or to co-culture them, said Bollag, who could not go into details as the company has filed a provisional patent covering its innovations, but claims that it has some compelling IP that will help it differentiate itself in the nascent cell-based meat industry.

Were working on a portfolio of patents to reinforce this main patent. Were still working out which is the best method to use at scale, but our next prototypes will include fat [from animal cells rather than plants] if not more cell types [as well as muscle] in the mix.

However, the process of reprogramming adult stem cells to behave like embryonic master cells does not involve genetic engineering, a key factor for any company trying to enter the European market, stressed Bollag, who anticipates bringing products to market in 2-5 years, perhaps beginning in high-end restaurants in the EU, where cell-cultured meat would be considered a novel food and therefore subject to pre-approval under the Novel Food Regulation.

We have some more work to do before we would submit a Novel Food application, and then it might take another year and a half [for the approval process]

She added:Were a technology company, so well launch on a small scale, but for a larger scale launch, we want to partner with larger organizations to leverage their expertise in distribution, packaging and consumer insights and so on and then the productscould be [launched under]our brand or their brand or a co-brand.

She would not go into details on materials Higher Steaks is exploring as scaffolding (edible structures upon which firms can seed cells in order to grow more 3D structures), but said Higher Steaks is testing several materials.

There are also a lot of new companies popping up sending us their scaffolds to test, which is really exciting.

As for finding alternatives to fetal bovine serum that can serve as cost-effective growth media (ie. food for the cells), she said: We have very clear pathways on how to get the cost down of both the growth media [to help the stem cells proliferate] and the differentiation media [to signal them to differentiate and mature into different cell types such as fat, muscle etc].

One of the things is reducing the number of growth factors you need, and there are specific things were working on internally, but there are also a lot of companies working in this space so its an area for collaboration.

The decision to focus on pork was made for multiple reasons, said Bollag, who is currently backed by some very supportive angel investors: Pork supply is under significant threat because of African swine fever and on top of that, a lot of antibiotics used[in meat production]are used in pork and poultry, and one of the main challenges we are trying to address is antibiotic resistance.

Pork is also used in a ton of processed products such as sausages that are easier to create [in bioreactors]than something like a [beef]steak. Its also genetically similar to humans, so its easy to adapt the work that has been done on the medical side[to large scale cell-based meat production].

As to what to call meat cultured from animal cells, Bollag says shes happy with the terms cell-based meat, and cultivated meat, adding: Its really about finding something that works for consumers and regulators but doesnt alienate the meat producers but also describes the product accurately.

Cell-based meat: From the laboratory to the market

Despite all the hype, most startups in the space are still working in a laboratory (as opposed to a factory), although several have recently raised more substantial sums (Memphis Meats: $161m,BlueNalu: $20m,Future Meat Technologies: $14m,Wild Type: $12.5m,Aleph Farms: $12m,Meatable: $10m) to support the construction of pilot-scale facilities.

Maastricht-basedMosa Meat which is gearing up for a small scale commercial launch in 2022 assuming it has cleared regulatory hurdles - recently joined forces with Nutreco (which has invested an undisclosed sum in the firm along with Lower Carbon Capital) to work on growth media; San Diego-basedBlueNaluhas also partnered with Nutreco and aims toproduce small quantities of product for commercial launch in late 2021; while Jerusalem-basedFuture Meat Technologiesplans to release hybrid products in 2021 and a second line of 100% cell-based ground meat products suitable for burgers and nuggets at a cost ofless than $10 per pound in 2022.

However, the recent$161m investment in Memphis Meats- which says it has a pretty clear pathto achieving cost parity with conventional meat has given the whole sector a confidence boost, says Krijn de Nood, CEO at Dutch cell-based meat startupMeatable.

Its a huge positive for the industry, it shows there are very serious investors that have done their due diligence and think this is really going to happen.

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Hybrid products could drive first wave of cell-based meat launches, predicts Higher Steaks as it unveils pork belly, bacon prototypes -...

Edited Transcript of RQE.L earnings conference call or presentation 20-Jul-20 11:00am GMT – Yahoo Finance

Surrey Jul 20, 2020 (Thomson StreetEvents) -- Edited Transcript of ReNeuron Group PLC earnings conference call or presentation Monday, July 20, 2020 at 11:00:00am GMT

* Richard L. Beckman

Hello, and welcome to the ReNeuron Preliminary Results Conference Call. (Operator Instructions) And just to remind you, this conference call is being recorded.

Today, I'm pleased to present Olav Helleb, CEO. Please go ahead with your meeting.

Thank you very much. Good morning, and thanks, everyone, for joining this analyst meeting. I hope everyone is well, and we look forward to having one of these face-to-face again before too long.

Before we start digging into the presentation, if you do not have a copy of the slides, please go on to our website. There should be a link at the front page there or in the investor section where you can find the slides that will be easy to follow.

So let's start by turning to Slide #2. This is the disclaimer, so please note that. Then we'll jump to Slide #3. As you know already, ReNeuron is a leading cell therapy company. We're present in the U.K. and the U.S. And we have allogeneic, retinal and neural stem cell technology platforms. And we also have exosomes and pluripotent stem cells. Our lead program is in Phase II in retinitis pigmentosa, and we expect to partner that program when this Phase II study is completed.

There's now increasing focus on exosomes out there and also from our side and iPSCs as well. So we have already a number of research collaborations ongoing there, and we expect to have more of those going forward.

Let's have a look at the platform technologies on Page 4. So human retinal progenitor cells is our lead program. These are subretinal-delivered stem cell store, and we deliver them subretinally in order to enable engraftment, which has the best potential both in terms of efficacy and improved vision and also long-term efficacy. The cryopreserved formulation that we have developed and are currently using in the clinical trials allows for global ship and store. So these have a 9-month shelf life. We can ship them anywhere in the world. They're delivered in shipping containers that have 10 days dating on them so that we can really get them anywhere we need to get them. So that's obviously good for clinical trials, but even better for commercial launch.

The data we have so far is very positive in retinitis pigmentosa, which is our first indication. This program is unencumbered, except in China, where we have partnered up with Fosun Pharma. the exosome platform is -- comes from CTX. So it's a high-yielding platform. We have proven the ability to load this exosome with different modalities. And we also have proven that these exosomes are happy to go across the blood-brain barrier, so -- which is a big medical need. We are focusing on exosomes as a delivery vehicle. There are other potential uses as well. But for us, that is the focus.

The iPSC platform is also coming from CTX, so this is pluripotent stem cell platform, and we can engineer CTX stem cells into other forms of stem cells. And the potential here is -- are for new cell therapeutics based on this platform.

CTX cells you know well. We had positive Phase IIa results that was just -- was published in this financial year. Also published out there are potentials in other indications such as Huntington's. This program is partnered with Fosun for China, and it's available for licensing in other geographies, which is our strategy now for CTX.

The development pipeline is on Page 5. So you can see here that the retinitis pigmentosa program is on top of the list. We will have further readouts coming both this year and next year. This is an open-label study, so we're able to have a look continuously, and we'll update the market as and when required.

CTX, as I already mentioned, in stroke disability, the clinical development there is with Fosun for China the -- and other potential partnerships either for stroke or for Huntington's.

The exosome platform is in a preclinical phase with a number of different approaches. The next milestone there is proof-of-concept data. We have several shots on goal in order to deliver that over the next 6 to 12 months.

In iPSC, the focus is more about validation of the technology itself, and we're looking forward to preclinical proof-of-concept data also for that platform.

So with that, we'll skip to the operational highlights on Page 7. This is straight from today's RNS. So apologies for the slide. Busy slide, but yes, you have it in the RNS. You can read it at your convenience. These are the highlights for the last financial year.

For hRPC, we have sustained, efficacy throughout all-time points so far in the study that's ongoing. We have received regulatory approval to expand this study both in the U.S. and the U.K. And U.K. -- so far, the study has been in the U.S. only, so it's great that we can add the U.K. in here as well. We will have further readouts coming over the next 12 months. And the next step after this Phase IIa study is to agree with the regulatory agencies about a single pivotal trial that will lead to approval.

Exosomes. We have a number of collaborations ongoing using our exosomes as a delivery vehicle. We also presented new data on our induced pluripotent stem cells. This year, and we've signed collaborations on the exosome with major pharma/biotech companies, unnamed so far. These collaborations are mainly focused on delivering across the brain -- blood-brain barrier, whatever therapeutic these companies are interested in delivering.

We also have a COVID-19 vaccine delivery platform in development, which may come -- become very useful, depending on how the first vaccines -- how effective they are. And we hope to see them soon. But I think the common perception about COVID-19 vaccines is that the first ones will not be fully effective. And that's when delivery systems like this one can come in handy.

CTX cells. So yes, PISCES II was published this year. We have decided to continue this drug feasibility program through regional partnerships. Fosun Pharma in China is continuing their work on CTX. The PISCES III study in the U.S. was suspended due to COVID-19. This suspension was quite obvious since our patients there are disabled and had no business running in and out of hospitals during this time. So it was a natural suspension.

We have decided to remain in a suspended state for that study. It is both a great indication and an excellent product and a perfectly designed clinical trial. However, it is also very research -- resource-intensive for us. And we rather invest those resources in what we think are the 2 most promising programs in the mid -- short and medium term, which is in ophthalmology and exosomes. So for that reason, we decided to keep PISCES III suspended in the U.S., and we will not restart that unless it's funded by a partner.

So with that, I will hand over to Michael for the financials on Page 8. Michael?

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Michael E. Hunt, ReNeuron Group plc - CFO, Company Secretary & Executive Director [3]

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Thanks, Olav. Yes, I'm Michael Hunt. I'm Chief Financial Officer of ReNeuron, for those of you that don't already know me.

So Slide 8 just gives a summary of the preliminary results that we've announced this morning for the year ended March 2020. And we've shown the prior year comparatives here as well.

In terms of the underlying cost base, it's broadly similar to the prior year. As you can see, slight saving on G&A costs. And importantly, as Olav has just mentioned, the fact that we have now decided to make our stroke program essentially an outsourced endeavor under partnerships, that will have a consequent significant effect on our prospective cost base going forward. So we do expect to see our underlying cost base reduced significantly from what you see here in the numbers reported to March this year. The numbers you see here are also somewhat flatted by the upfront payment we received from Fosun when we signed that licensing deal for China in April last year. So that payment just made it into the numbers we're reporting on. And that's a large part, a very significant part actually, of the GBP 6 million -- or GBP 6.1 million you see on the top line.

Cash on hand at the end of March this year was GBP 12.6 million, as you see, and that gives us around about a year's cash from where we are now, maybe slightly less than 1 year. So we are reasonably well financed for the time being. And importantly, we do expect to garner further milestone payments from that Fosun deal and hopefully other deals that we sign going forward over the next year to 18 months. In the case of Fosun, that they continue to make progress with both our retinal and our CTX stroke program in China.

And with that, I'll hand back to Olav. Thank you.

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Olav Helleb, ReNeuron Group plc - CEO & Director [4]

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Thank you, Michael. Yes, I think I will now ask Rick Beckman, our Chief Medical Officer, to take you through the RP program. Rick happens to be an ophthalmologist and what he doesn't know about RP is probably not worth knowing. Over to you, Rick.

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Richard L. Beckman, ReNeuron Group plc - Chief Medical Officer [5]

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Thank you, Olav. If you turn to Page 10, we'll talk a little bit about our hRPCs, human retinal progenitor cells. hRPCs are no longer stem cells. They've already differentiated along the pathway. As such, they can only go on to become the cellular elements of the retina, particularly the photoreceptors, which are responsible for capturing a light impulse and turning it into an electric stimulus that goes on to the brain and that supports sight. We've shown in preclinical models that we have cells that integrate into the anatomic layers of the retina.

And we believe -- and we've also shown that they actually integrate and differentiate into photoreceptors. We believe that there's 2 modes of action: one is differentiation and performing photoreceptors and replacing cellular material; but the other mode of action is integration and providing trophic support. And by integrating, we believe that we can have a significantly durable source of trophic support, sort of a depot, if you may. We think that this type of technology is viable for a variety of eye diseases. Currently now, we're going after retinitis pigmentosa, and I'll talk a little bit more about that.

We have orphan drug designation in both the EU and the U.S. RP is a very large orphan population, but it is still an orphan disease. The proprietary manufacturing is what sets us apart from our competitors. This is from a collaboration between Schepens Eye Research Institute and University College of London. And we have a GMP manufacturing process. But the most important take-home point is that we have cryopreserved cells. Our competitor has not been able to develop cryopreserved cells. This is important clinically because, instead of having to fly your patients to be within 12 hours of one manufacturing site, we can ship these cells to anybody's surgical center throughout the world. They have a 9-month shelf life.

If you'll turn to Page #11, for those of you who are not familiar with retinitis pigmentosa, it's a very large unmet need. It has an incidence of about 1 in 4,000, which means, in the United States, there's some 80000-or-so patients and in EU somewhere between 130,000 and 150,000 patients, which makes it a large orphan disease. There have been over 100 genes which have been identified as causing mutations that could lead to this clinical syndrome. And you're probably aware that there is one treatment now available, that's Luxturna, for the single gene defect, RPE65.

The most important thing to understand about that is it's only a low single-digit number of patients that are able to be accessed, meaning in the range of 2% of patients will have one of these defects that people are working on right now. For Luxturna, it's probably about 2% of the population. There are multiple companies that are now working in this space going after one of these genetic defects. And that shows you that there's a very large commercial market potentially for this. But of all those defects, you're also talking about trying to access low-single-digit percentage of the patients. We believe that by using the cellular method that we are agnostic to the genetic type and therefore can go after the entire market in RP.

So the important thing to understand about retinitis pigmentosa is that patients start developing symptoms in their teens, sometimes a little bit later. And their first symptom is generally night blindness, meaning when they go into a dark room, they're not able to adapt to seeing well. This isn't that terrible. However, then it starts to rob them of their peripheral vision, which is very concerning to people. And the most important point is that these people, they know that they're slowly going blind. They get diagnosed. They look at the familial components. And aside from genetic counseling and future planning in the vast majority of these people, there's nothing that could be done. And by the time they reach their 40s and 50s and 60s, the most productive years of their life, their vision is being taken from them and they see it going away.

And so in terms of enrolling a clinical trial, clinical trials are easy to enroll because there's a list of patients who have been waiting for something available. And with their increased knowledge right now that there's a therapy available for some of them, everybody has a significant interest in being involved because there's no treatment available.

If you look at Slide #12, this is just to show you the landscape of companies that are participating in this disease. The only real competitor, and we actually think of them as somebody that's validating the principle, is a company called jCyte. jCyte uses a similar cell. However, they implanted it into the center of the eye, into the vitreous. And because it's not being implanted in the anatomic position where the cells are, we don't believe that integration and differentiation is possible. So the mechanism of action for them would just be providing trophic support, which is possible from the vitreous, but we haven't seen their data, but we're looking forward to seeing that relatively soon.

We, on the other hand, implant ourselves subretinally into the anatomically correct position such that the cells can integrate into the retina actually shown in preclinical models and differentiate and also potentially sit there and be a little biofactory for trophic factors that support the other cells.

The other players in the market are going after the gene therapy approach. And as I said, if you put all of them together, and a lot of them are going after the same disease because there's only certain RP variants that are amenable to gene therapy. Remember, you're not replacing cells. So what you have to be doing is stopping the degenerative process and potentially reviving cells that are not yet dead. They're going after the small, but there's a very large commercial value to that, as you can see from the Spark and the Nightstar acquisitions.

Going to Slide #13. I'll just take us briefly through our clinical development to date. We started off about 3 years ago at Mass Eye and Ear Infirmary in Boston with a Phase I single-ascending dose study. So what we did is took 12 patients. We treated them. The first 3 patients received 250,000 fresh cells, then we went to 0.5 million fresh cells, then we converted to a cryopreserved formulation and treated an additional 6 patients such that they were getting 1 million cells.

Our data safety monitoring board, the regulatory authorities and our investigators felt comfortable at that point then moving into a different patient population. The first group of patients were all people who had very, very severe disease, very little remaining vision. None of them were really able to see letters on a chart. And this was done because of safety. We didn't want them to have a lot to lose. But consequently, they didn't really have much to gain. Because we believe there has to be some remaining in that and be present in order to have integration of the cells.

We next moved into a Phase IIa study, and I'll be showing you some of the data from that. That's 10 patients with established RP. They had better visual potential. And consequently, they also had some vision to lose. They received 1 million cells subretinally. Primary endpoint was safety, although we started looking at efficacy.

And just to summarize before I get into the data, I think what we've shown is that we've been able to achieve visual acuity results that would be consistent with an approval in the United States and the EU if we can replicate those in a much larger clinical study. But before we go into that larger clinical study, the decision was made to provide -- to go into 90 different patients in a study that's designed to really substantiate and further bolster the data that we have because we'll be going into a much larger clinical trial. Hopefully, we believe the pivotal clinical trial at the completion of this.

If you go into Slide 14, this shows you the data to date, and I want to show you a few things to separate out this data from what we presented back in February. The first thing is we now have 1 patient that has made it out to 18 months. And one of the questions that we've been getting from people all along is how long is it going to last? One of the values of having an open-label study is we get some readouts and some learnings as we move along. However, the -- this service provided by open-label studies, you don't get to look at the data at the end in aggregate. And so you see little things happening during the middle that can point you potentially in the wrong direction.

But what we've shown in this data now is a separation. If you look at the light blue line, that's the mean change in visual acuity in the treated eye. The dark blue line is the mean change in visual acuity in the non-treated eye. And this is all measured by ETDRS visual acuity. An ETDRS chart is very similar to the Snellen chart that you use when you go to the eye doctor to have your eyes checked, except it's been adapted for doing clinical trials, meaning it's been substantiated. All of the letters are the exact same size. All of the letters are equally difficult to see between each other.

There's a standard number of size at each line. Each line is a logarithmic distance from the line before. So all of the statistical things could be done more. Basically, as you read down the line, the letters get smaller and it takes better visual acuity to be able to differentiate the smaller letters. So when you go to additional letters, we consider that a letter game, meaning that each time you're able to read up smaller letters, you've improved in your visual acuity.

And what you see is that, at all-time points, we show a differentiation between the treatment eye and the untreated eye. And we're showing a very significant amount of visual gain in most patients. To get a drug approved in the United States, people will say that they consider clinical significance to be a 15-letter or 3-line change. That doesn't mean that you have to have a mean change of 15 letters to get a drug approved. Actually, all of the anti-VEGF drugs were approved, and their mean changes were between 8 and 10 letters, some even a little bit lower. What it does mean, though, is that you probably need to show a statistically significant difference between the percentage of patients in your treatment group that are seeing a clinically significant change versus that percentage in your control group. And in this particular disease process, control patients do not generally gain vision.

Now one of the things that people were concerned about early on in our data is we've shown that there is some improvement in vision in some of the patients in the untreated eye. And that's one of the things that we've worked on for the additional 9 patients because we had 1 particular patient which showed a very significant learning curve, up to 20 letters at one point. And with a small n, you can see that, that makes the mean very significant. We don't believe that, that's a true effect. We believe that that's part of the learning curve. And so when we design the additional 9 patients, we now are very careful with getting multiple baseline readings prior to treatment so that we can eliminate anybody with a learning beforehand.

Another thing that you're going to see with this data here is that we're excluding 1 patient with surgery-related vision loss. If some of you remember well, when we presented the data back in February, we excluded 2 patients with surgical-related vision loss because we didn't think that they showed the real effect of the drug therapy. This is a well-established surgical procedure, but it's still a very delicate surgical procedure. And these eyes are very thick eyes, meaning that they've had a lot of anatomic scar changes occurring to the retina.

And so nobody in the ophthalmic community is concerned with the surgical complication rate in the rate of 5% to 10%. Because from a risk/benefit potential, there's no potential gain in these eyes. They're all going blind, and there is a very significant potential benefit. However, as you can see, right now, we're only excluding 1 patient with surgically related vision loss because one of the patients, the reason why their vision has declined is they developed a clouding of the lens following surgery, which is not uncommon with retinal surgery.

And the simple procedure removing their cataract, which is one of the most common procedures that we do in ophthalmology, probably the most common, resulted in their vision now crossing over, and that now they've gained vision. And so the effect that they have is, in the earlier months, they're bringing the visual acuity, the mean change down a little bit because they were a vision loser down to about 20 letters or so of vision loss. But as the data progresses and their vision has now improved, you'll start to see more of a separation of those lines. Again, that's the effect of looking at data day-to-day in an open label as opposed to just looking at it at the end when it's all in front of you.

So now we have a surgical complication rate of 1 in 22, which is about 4% to 5%. And nobody in the ophthalmic community is concerned about that. We'd rather have none, but it is a surgical procedure, and we are humans.

I'm going to go onto the next slide now, which is the design of the Phase IIa extension study, and I've already alluded to some of the components. One of the past criticisms that we've had from potential partners is, "Hey, we get it. You've got really good efficacy, and we believe that you can be approved on efficacy alone, but we'd like to see that corroborated by some other indicator of efficacy." And during conversations with our scientific advisory board and particularly Dr. [McFerran], who's now come on as one of the investigators from Oxford, who is involved in the formation and prosecution of Nightstar, it turns out that visual acuity was more difficult to achieve in those patients than the efficacy indicated that it was successful was microperimetry.

And microperimetry is a measure of retinal sensitivity and what you do is you focus the camera and light source at specific elements of the retina and you stimulate the same point at levels of illumination, which are too dim to be seen and then you ratchet it up until the eye can just barely see it. And by doing that, you can map out the sensitivity of the different retinal points.

Now what they did, which is very nice, and what we're doing in this study, is we're now only including patients that are capable of consistently repeating and performing the microperimetry test. And that will probably kick up the average visual acuity of our patients a little because, in general, with RP, it's the patients that still have more remaining vision that are able to fixate and take that test. So the study with the extra 9 a -- 9 additional subjects is designed to give us a -- another efficacy indicator to substantiate the visual acuity movements that we've already seen.

Finally, as I told you, we're doing additional baseline so that we're not going to establish a learning curve. And we've also eliminated a symmetry between the 2 eyes that they have more than a 20-letter difference between the 2 eyes we don't include them, just so people can't say that that's regression to the mean or anything like that.

Finally, what we've done is we've modified the surgical technique, and this is a really important minor detail to most people, but a major detail to the surgeons doing the surgery. We've doubled the dose to 2 million cells. The reason being is we've seen no dose-limiting toxicity. The regulatory agencies prefer it. And we also want to see if the reason why some patients have had a tremendous response and some have only had a moderate response could be a question of dose.

So we've increased the dose. We're now going to create 2 different surgical blebs underneath the retina. But the design now, unlike the previous patients who we treated. Previously, we treated patients, and we tried to deliver the cells right to the areas of the retina where we had remaining functional retinal tissue. And that's important because we want the cells in that area. But the difficult part of that is that, when you lift them off by creating a little blister underneath the retina for the fluid, which takes a few days to reabsorb, you're also separating them from their nutritional supply. So it's potential for a double-edged sword.

What we're doing now is we're going to be very carefully placing those blisters so that we have the edge of the blister in nonfunctional tissue, but getting very close to the functional tissue, with the idea being we'll get the cells very close to where we need them, but we're not going to be causing a separation of the retina. And we -- and potentially, that will give us a little better efficacy. So I believe and we believe, and our advisory board and investigators believe, that we've set up a very, very nice additional study to substantiate the data that we have from the earlier studies. And to use my own parlance, I think we have a very, very accurate shot on goal that is prepared.

And if you turn to Slide #16, we believe that we're going to get started on this imminently. We do have approval from both the EU -- U.K. and the U.S. regulatory authorities. We're in the process of getting patients set up. And hopefully, we'll be doing something in August or early September. Remember, right now, a lot of centers are closed down because of COVID, which has caused a significant delay. But if our plans work out, and we're pretty confident they will, then we'll get started within the next month or 2. And we anticipate having top line data to present sometime around this time next summer. However, if there's something material that happens beforehand, we'll be presenting something earlier than that.

I think that I have -- oh, yes, and the idea would be to submit to the regulatory agencies to go into a potential pivotal clinical trial, submitting sometime at the end of 2021 and potentially getting started very early in 2022 at a pivotal trial. That's all I have. So I'll turn it back to Olav.

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Olav Helleb, ReNeuron Group plc - CEO & Director [6]

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Thank you, Rick. And yes, just to remind everyone that there will be an opportunity for Q&A at the end. Obviously, the RP portion is the key portion of this presentation. But let's have a look at exosomes and the iPSCs as well.

So on Page 18, just a quick primer on what exosomes are. So they're naturally occurring communication devices released by cells. We and others have demonstrated that these nanoparticles can be loaded with different cargoes to deliver, very efficiently, therapeutics to specific tissues. And this will overcome many hurdles that you see with the gene therapy, and I'm talking then about hurdles or disadvantages just really of the viral vector delivery system that gene therapies are using.

On Page 19, ReNeuron has years of experience around manipulation and culture of cell lines. The CTX cell line in particular, is easily to be modified so we can allow engineering and introduction of new payloads. And the c-mycER immortalization technology is key to that. It creates consistency of the product. And the stable cell line results in the stable exosome product. So we've shown that our exosomes will and can cross the blood-brain barrier. We've proven an ability to load micro RNAs and proteins. We've shown stable and consistent high-yield production, and we've shown that we can carry various payloads and also engineer to target specific tissues.

And that results in the pipeline on Page 20 of several exosome products and also some iPSC platform technologies. As examples of the exosome, so this is all about loading something into the exosome. The exosome is the delivery vehicle. And then we have a payload loaded into that.

ExoBDNF. As an example, this is an exosome that's engineered to express the neuroprotective growth factor, BDNF, brain-derived neurotrophic factor. That's been sitting on the surface of the exosome. And BDNF has been implicated in Parkinson's, Alzheimer's, but also hearing loss and glaucoma. The second here is ExoKRAS. this is an exosome engineered to deliver the sRNA against KRAS G12D gene mutation, which is found in a number of cancers, particularly glioblastoma and pancreatic cancer.

The third one down is exoSPIKE. This is an exosome that's engineered to express the SARS-CoV-2 spike protein on the surface of the exosome, and that aim -- that assists for the delivery of a prophylactic vaccine. It is a targeted delivery directed to the lymph nodes, and that stimulates strong immune response. So this has a great potential for delivery of -- sorry, COVID vaccines. Hopefully, Moderna or some of the other companies will take care of it all very quickly, but the chances are that that's not going to happen and improved delivery systems will be needed. In that case, this will be a very important program.

Well, the fourth one down is a collective of different approaches that we have. This is exosomes that are loaded with therapeutics of partners. So we have signed research collaborations with large biotechs. They have certain payloads they would have -- like to have delivered into the brain. That's obviously a very difficult thing to do. And what these partnerships are focused on is that our partner will send us payloads. And sRNA being a typical payload, we put them into our exosomes. We send them back to our partner. The partner then runs studies in the lab and then animal studies to see if this will solve the delivery issue. And if that -- if the payload is actually active on the inside, any proof-of-concept on any of these collaborations will be extremely valuable in validating the entire exosome platform.

So they're ongoing, and we expect to sign more. This is a very hot area for research. So I'll touch more on the iPSCs a bit later, but let's have a look at deals done in exosomes, first of all, on Page 21. So like I mentioned, the -- there's a lot more attention now for research around exosomes as an alternative to viral vectors. There are 2 pure-play exosome companies of note. One is Codiak Therapeutics in Boston. The other one is Evox Therapeutics in Oxford. Between them, this -- they have signed 4 major deals.

The Codiak/Sarepta one was just 2 weeks ago. That was a total of $72 million in research payments for Sarepta to -- that Sarepta paid in order to investigate 5 different neuromuscular targets. So -- and just in technology access and research payments, that's -- the $72 million, that's more than our market cap. So these deals are as significant when you consider that nobody is in the clinic yet. It's all in research.

Then the -- I guess the natural question is, what does Evox and Codiak have that ReNeuron doesn't? And the answer is proof-of-concept data in an animal model. And we're working feverishly on delivering that. You saw that on the previous page. We have 2 internal programs, one of them grant-funded. And we have several programs also with partners. So we have a number of shots on goal over the next 6 months or so to deliver on that.

A bit more on iPSCs on Page 22. So iPSCs are ideal material to produce themselves both the cell therapy and for -- to produce exosomes. They have the potential to differentiate into any of the 3 germ layers. However, they're unstable. Differentiation are -- is difficult and never 100% efficient. So for us to overcome these barriers, we have reprogrammed our CTX cell line to improve the potency. And what that has resulted is actually that the c-mycER immortalization technology is continued through this change in reprogramming. And that is very, very useful because that means that now we have been able to put that stability into the iPSCs and we can create off-the-shelf cell therapy products as a starting material for -- to produce cells such as T cells for CAR-T therapy, for example.

So there are 2 programs that we are developing right now. One is immortalized haematopoietic stem cells. So this is to provide a stable intermediate for these T-cells or NK cells, as I mentioned. And the other was the pancreatic progenitor cell for the generation, again, of a stable pancreatic progenitor that could be used in diabetes. So these are early research programs, and the goal is very much to validate the technology and have -- and create a cell line that we can take forward.

Lastly, let's go to CTX on Page 24. I just want to reiterate that our strategy for CTX going forward is a licensing strategy. So we, obviously, are committed to support Fosun for their work on CTX in China. And we're also looking at out-licensing for other potential territories as well as the Huntington disease potential indication where we have published some interesting animal data.

Last page, Page 26. Just a quick summary before we go to Q&A. So ReNeuron, as you know, is a global leader in cell-based therapeutics. Our platforms are allogeneic. They're patented and high-yielding. Ophthalmology is an area of great industry interest, and the RP Phase II study has produced excellent results so far, which has led to this study to be expanded. Another hot area is exosomes, and we are well positioned here to generate validating proof-of-concept data and then partnering deals following that.

So that concludes the presentation. I suggest we go to Q&A. I now hand over to the operator to take us through the -- how that works.

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Questions and Answers

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Operator [1]

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(Operator Instructions) Our first question comes from the line of Christian Glennie from Stifel.

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Christian Glennie, Stifel, Nicolaus & Company, Incorporated, Research Division - Analyst [2]

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Three questions, if I may, and just take them in order, if that's okay. Firstly, on the expansion, just looking ahead to the RP trial and expansion of that trial. You obviously talked about the -- with COVID restrictions. But what's the potential timing of that -- starting that trial and actually getting those 9 patients treated? And potentially, you'll have sort of 4 sites, 2 -- [still] 2 in U.S. and an extra in the U.K., I think.

And as part of that expansion, did you consider on a higher dose, but did you consider a redosing at any point? Or are you thinking actually the longevity of the data you've seen so far suggests that maybe that may not be necessary?

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Originally posted here:
Edited Transcript of RQE.L earnings conference call or presentation 20-Jul-20 11:00am GMT - Yahoo Finance

Global Regenerative Medicine Market: Size and Forecast with Impact Analysis of COVID-19 (2020-2024) – Jewish Life News

Scope of the Report

The report titled Global Regenerative Medicine Market: Size & Forecast with Impact Analysis of COVID-19 (2020-2024), provides an in-depth analysis of the global regenerative medicine market with description of market sizing and growth. The analysis includes market by value, by product, by material and by region. Furthermore, the report also provides detailed product analysis, material analysis and regional analysis.

Access the PDF sample of the report @https://www.orbisresearch.com/contacts/request-sample/4707408

Moreover, the report also assesses the key opportunities in the market and outlines the factors that are and would be driving the growth of the industry. Growth of the overall global regenerative medicine market has also been forecasted for the years 2020-2024, taking into consideration the previous growth patterns, the growth drivers and the current and future trends.

Some of the major players operating in the global regenerative medicine market are Novartis AG, Medtronic Plc, Bristol Myers Squibb (Celgene Corporation) and Smith+Nephew (Osiris Therapeutics, Inc.), whose company profiling has been done in the report. Furthermore, in this segment of the report, business overview, financial overview and business strategies of the respective companies are also provided.

Region Coverage

North America Europe Asia Pacific ROW

Company Coverage

Novartis AG Medtronic Plc Bristol Myers Squibb (Celgene Corporation) Smith+Nephew (Osiris Therapeutics, Inc.)

Executive Summary

Regenerative medicines emphasis on regeneration or replacement of tissues, cells or organs of human body to cure the problem caused by disease or injury. The treatment fortify human cells to heal up or transplant stem cells into the body to regenerate lost tissues or organs or to recover impaired functionality. There are three types of stem cells that can be used in regenerative medicine: somatic stem cells, embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells).

The regenerative medicine also has the capability to treat chronic diseases and conditions, including Alzheimers, diabetes, Parkinsons, heart disease, osteoporosis, renal failure, spinal cord injuries, etc. Regenerative medicines can be bifurcated into different product type i.e., cell therapy, tissue engineering, gene therapy and small molecules and biologics. In addition, on the basis of material regenerative medicine can be segmented into biologically derived material, synthetic material, genetically engineered materials and pharmaceuticals.

The global regenerative medicine market has surged at a progressive rate over the years and the market is further anticipated to augment during the forecasted years 2020 to 2024. The market would propel owing to numerous growth drivers like growth in geriatric population, rising global healthcare expenditure, increasing diabetic population, escalating number of cancer patients, rising prevalence of cardiovascular disease and surging obese population.

Though, the market faces some challenges which are hindering the growth of the market. Some of the major challenges faced by the industry are: legal obligation and high cost of treatment. Whereas, the market growth would be further supported by various market trends like three dimensional bioprinting , artificial intelligence to advance regenerative medicine, etc.

Browse the full report @https://www.orbisresearch.com/reports/index/global-regenerative-medicine-market-size-and-forecast-with-impact-analysis-of-covid-19-2020-2024

Table of Contents

1. Executive Summary

2. Introduction

2.1 Regenerative Medicine: An Overview 2.2 Regeneration in Humans: An Overview 2.3 Expansion in Peripheral Industries of Regenerative Medicine 2.4 Approval System for Regenerative Medicine Products 2.5 Regenerative Medicine Segmentation

3. Global Market Analysis

3.1 Global Regenerative Medicine Market: An Analysis

3.1.1 Global Regenerative Medicine Market by Value 3.1.2 Global Regenerative Medicine Market by Products (Cell Therapy, Tissue Engineering, Gene Therapy and Small Molecules and Biologics) 3.1.3 Global Regenerative Medicine Market by Material (Biologically Derived Material, Synthetic Material, Genetically Engineered Materials and Pharmaceuticals) 3.1.4 Global Regenerative Medicine Market by Region (North America, Europe, Asia Pacific and ROW)

3.2 Global Regenerative Medicine Market: Product Analysis

3.2.1 Global Cell Therapy Regenerative Medicine Market by Value 3.2.2 Global Tissue Engineering Regenerative Medicine Market by Value 3.2.3 Global Gene Therapy Regenerative Medicine Market by Value 3.2.4 Global Small Molecules and Biologics Regenerative Medicine Market by Value

3.3 Global Regenerative Medicine Market: Material Analysis

3.3.1 Global Biologically Derived Material Market by Value 3.3.2 Global Synthetic Material Market by Value 3.3.3 Global Genetically Engineered Materials Market by Value 3.3.4 Global Regenerative Medicine Pharmaceuticals Market by Value

4. Regional Market Analysis

4.1 North America Regenerative Medicine Market: An Analysis 4.1.1 North America Regenerative Medicine Market by Value

4.2 Europe Regenerative Medicine Market: An Analysis 4.2.1 Europe Regenerative Medicine Market by Value

4.3 Asia Pacific Regenerative Medicine Market: An Analysis 4.3.1 Asia Pacific Regenerative Medicine Market by Value

4.4 ROW Regenerative Medicine Market: An Analysis 4.4.1 ROW Regenerative Medicine Market by Value

5. COVID-19

5.1 Impact of Covid-19 5.2 Response of Industry to Covid-19 5.3 Variation in Organic Traffic 5.4 Regional Impact of COVID-19

6. Market Dynamics

6.1 Growth Drivers 6.1.1 Growth in Geriatric Population 6.1.2 Rising Global Healthcare Expenditure 6.1.3 Increasing Diabetic Population 6.1.4 Escalating Number of Cancer Patients 6.1.5 Rising Prevalence of Cardiovascular Disease 6.1.6 Surging Obese Population

6.2 Challenges 6.2.1 Legal Obligation 6.2.2 High Cost of Treatment

6.3 Market Trends 6.3.1 3D Bio-Printing 6.3.2 Artificial Intelligence to Advance Regenerative Medicine

7. Competitive Landscape

7.1 Global Regenerative Medicine Market Players: A Financial Comparison 7.2 Global Regenerative Medicine Market Players by Research & Development Expenditure

8. Company Profiles

8.1 Bristol Myers Squibb (Celgene Corporation) 8.1.1 Business Overview 8.1.2 Financial Overview 8.1.3 Business Strategy

8.2 Medtronic Plc 8.2.1 Business Overview 8.2.2 Financial Overview 8.2.3 Business Strategy

8.3 Smith+Nephew (Osiris Therapeutics, Inc.) 8.3.1 Business Overview 8.3.2 Financial Overview 8.3.3 Business Strategy

8.4 Novartis AG 8.4.1 Business Overview 8.4.2 Financial Overview 8.4.3 Business Strategy

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Global Regenerative Medicine Market: Size and Forecast with Impact Analysis of COVID-19 (2020-2024) - Jewish Life News