Knotty Problem of Cell Reprogramming Solved – Technology Networks

USC scientists have surmounted a big roadblock in regenerative medicine that has so far constrained the ability to use repurposed cells to treat diseases.

The researchers figured out how to reprogram cells to switch their identity much more reliably than present capabilities allow. The technique uses enzymes to untangle reprogramming DNA, somewhat similar to how a coiffeur conditions tangled hair. The technique works with near-perfect efficiency in mice and humans for all types of cells tested in the laboratories of USCs stem cell center.

The findings are significant because they clear an obstacle to help scientists find treatments for a wide range of diseases, especially neurologic impairments and conditions such as hearing loss.

This is a strategy for greatly improving our ability to perform cellular reprogramming, which could enable the regeneration of lost tissues and the study of diseases that cannot be biopsied from living patients today, said Justin Ichida, assistant professor in the department of stem cell biology and regenerative medicine at the Keck School of Medicine of USC.

The findings appear in Cell Stem Cell in a research paper titled, Mitigating antagonism between transcription and proliferation allows near-deterministic cellular reprogramming. Ichida is the lead author, joined by a team of researchers at the Keck School of Medicine.

How USC researchers untangled cellular reprogramming

Cellular reprogramming has enormous potential as a disease cure because it enables scientists to study cells and molecular processes at each step of disease progression in controlled conditions that have, until now, been impossible.

Reprogramming involves changing one cell into another type of cell, such as a blood cell into a muscle or nerve cell. Thats important for medical research because the technique can be used to recreate tissues lost to disease and to study diseases in tissues that cannot be biopsied from living patients.

The technique has been known for decades but hasnt met its potential. According to the USC team, thats because DNA does not respond well when manipulated to change itself. DNA molecules are twisty by nature, due to the double helix configuration. Reprogramming DNA requires uncoiling, yet when scientists begin to unravel the molecules, they knot up tighter. As a result, nucleotides become much more difficult to work with and cells wont replicate properly, Ichida explained. Current untangling techniques only work 1% of the time.

Think of it as a phone cord, which is coiled to begin with, then gets more coils and knots when something is trying to harm it, Ichida said.

To smooth the kinks, the researchers treated cells with a chemical and genetic cocktail that activated enzymes called topoisomerases. The process works by using the enzymes to open the DNA molecules, release the coiled tension and lay it smoothly. In turn, that leads to more efficient cellular reprogramming, which increases the number of cells capable of simultaneous transcription and proliferation, which is needed to promote tissue growth. Its the equivalent of a DNA detangler that relaxes the tension of reprogramming transcription and makes it easier to replicate new cell colonies or tissues in a lab.

Understanding diseases at a cellular level

The technique has multiple advantages over existing current practice. For example, it worked nearly 100% of the time. It was proven in human and animal cells. It can be employed today in laboratories to study disease development and drug treatments. It has immediate utility for studying schizophrenia, Parkinsons, ALS and other neurological diseases; in those instances, new cells can be created to replace lost cells or acquire cells that cant be extracted from people.

Moreover, the technique does not involve stem cells; the reprogrammed cells are not brand new but the same age as the parent cell, which is advantageous for studying age-related disease. The reprogrammed cells may be better at creating age-accurate in vitro models of human disease, which are useful to study diverse degenerative diseases and accelerated aging syndromes.

The key is to understand development of disease at a cellular level and how disease affects organs, Ichida said. This is something you can do with stem cells, but in this case, it skips a stem cell state. Thats important because stem cells reset epigenetics and make new, young cells, but this method allows you to get adult cells of same age to better study diseases in aged individuals, which is important as the elderly suffer more diseases.

This latest advance in regenerative medicine complements other recent technological gains, including gene editing, tissue engineering and stem cell development. It represents a convergence in regenerative medicine moving scientists closer to treating many diseases. It has practical utility to accelerate targeted medical treatments and precision medicine.

A modern approach for disease studies and regenerative medicine is to induce cells to switch their identity, Ichida said. This is called reprogramming, and it enables the attainment of inaccessible tissue types from diseased patients for examination, as well as the potential restoration of lost tissue. However, reprogramming is extremely inefficient, limiting its utility. In this study, weve identified the roadblock that prevents cells from switching their identity. It turns out to be tangles on the DNA within cells that form during the reprogramming process. By activating enzymes that untangle the DNA, we enable near 100% reprogramming efficiency.

Reference:Babos, K. N., Galloway, K. E., Kisler, K., Zitting, M., Li, Y., Shi, Y., Ichida, J. K. (2019). Mitigating Antagonism between Transcription and Proliferation Allows Near-Deterministic Cellular Reprogramming. Cell Stem Cell. https://doi.org/10.1016/j.stem.2019.08.005

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Knotty Problem of Cell Reprogramming Solved - Technology Networks

Stem Cell Therapy Market Foraying into Emerging Economies 2017-2025 – Techdadz

Stem cells are found in all human beings, from the initial stages of human growth to the end of life. All stem cells are beneficial for medical research; however, each of the different kinds of stem cells has both limitations and promise. Embryonic stem cells that can be obtained from a very initial stage in human development have the prospect to develop all of the cell types in the human body. Adult stem cells are found in definite tissues in fully developed humans. Stem cells are basic cells of all multicellular animals having the ability to differentiate into a wide range of adult cells. Totipotency and self-renewal are characteristics of stem cells. However, totipotency is seen in very early embryonic stem cells. The adult stem cells owes multipotency and difference flexibility which can be exploited for next generation therapeutic options. Recently, scientists have also recognized stem cells in the placenta and umbilical cord blood that can give rise to several types of blood cells. Research for stem cells is being undertaken with the expectation of achieving major medical inventions. Scientists are attempting to develop therapies that replace or rebuild spoiled cells with the tissues generated from stem cells and offer hope to people suffering from diabetes, cancer, spinal-cord injuries, cardiovascular disease, and many other disorders.

The stem cell therapy market is segmented on the basis of type, therapeutic applications, cell source, and geography. On the basis of type, the stem cell therapy market is categorized into allogeneic stem cell therapy and autologous stem cell therapy. Allogeneic stem cell therapy includes transferring the stem cells from a healthy person (the donor) to the patients body through high-intensity radiation or chemotherapy. Allogeneic stem cell therapy is used to treat patients who do not respond fully to treatment, who have high risk of relapse, and relapse after prior successful treatment. Autologous stem cell therapy is a type of therapy that uses the person's own stem cells. These type of cells are collected earlier and returned in future. The use of stem cells is done to replace damaged cells by high doses of chemotherapy, and to treat the person's underlying disease. On the basis of therapeutic applications, the stem cell therapy market is segmented into cardiovascular diseases, wounds and injuries, musculoskeletal disorders, gastrointestinal diseases, surgeries, neurodegenerative disorders, and others. On the basis of cell source, stem cells therapy is segmented into bone marrow-derived mesenchyme stem cells, adipose tissue-derived mesenchyme stem cells, and cord blood or embryonic stem cells

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By geography, the market for stem cell therapy is segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa. North America leads the stem cell therapy market owing to rising awareness among people, early treatment adoption, and new product innovations. Europe is the second leading market for stem cell therapy due to development and expansion of more efficient and advanced technologies. The Asia Pacific stem cell therapy market is also anticipated to grow at an increasing rate owing to increasing healthcare spending, adoption of western lifestyles, and growth in research and development. Asia Pacific is the fastest growing region for stem cell therapy as several players have invested in the development of new stem cell technologies. These factors are expected to drive the growth of the stem cell therapy market globally during the forecast period.

The major player in the stem cell therapy market are Regenexx, Takara Bio Company, Genea Biocells, PromoCell GmbH, CellGenix GmbH, Cellular Engineering Technologies, BIOTIME, INC., Astellas Pharma US, Inc., AlloSource, RTI Surgical, Inc., NuVasive, Inc., JCR Pharmaceuticals Co., Ltd., Holostem Terapie Avanzate S.r.l., PHARMICELL Co., Ltd, ANTEROGEN.CO., LTD., The Future of Biotechnology, and Osiris Therapeutics, Inc. Rising demand for advanced stem cell therapies will increase the competition between players in the stem cell therapy market.

The report offers a comprehensive evaluation of the market. It does so via in-depth qualitative insights, historical data, and verifiable projections about market size. The projections featured in the report have been derived using proven research methodologies and assumptions. By doing so, the research report serves as a repository of analysis and information for every facet of the market, including but not limited to: Regional markets, technology, types, and applications.

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The study is a source of reliable data on:Market segments and sub-segmentsMarket trends and dynamicsSupply and demandMarket sizeCurrent trends/opportunities/challengesCompetitive landscapeTechnological breakthroughsValue chain and stakeholder analysis

The regional analysis covers:North America (U.S. and Canada)Latin America (Mexico, Brazil, Peru, Chile, and others)Western Europe (Germany, U.K., France, Spain, Italy, Nordic countries, Belgium, Netherlands, and Luxembourg)Eastern Europe (Poland and Russia)Asia Pacific (China, India, Japan, ASEAN, Australia, and New Zealand)Middle East and Africa (GCC, Southern Africa, and North Africa)

The report has been compiled through extensive primary research (through interviews, surveys, and observations of seasoned analysts) and secondary research (which entails reputable paid sources, trade journals, and industry body databases). The report also features a complete qualitative and quantitative assessment by analyzing data gathered from industry analysts and market participants across key points in the industrys value chain.

A separate analysis of prevailing trends in the parent market, macro- and micro-economic indicators, and regulations and mandates is included under the purview of the study. By doing so, the report projects the attractiveness of each major segment over the forecast period.

Highlights of the report:A complete backdrop analysis, which includes an assessment of the parent marketImportant changes in market dynamicsMarket segmentation up to the second or third levelHistorical, current, and projected size of the market from the standpoint of both value and volumeReporting and evaluation of recent industry developmentsMarket shares and strategies of key playersEmerging niche segments and regional marketsAn objective assessment of the trajectory of the marketRecommendations to companies for strengthening their foothold in the market

Note:Although care has been taken to maintain the highest levels of accuracy in TMRs reports, recent market/vendor-specific changes may take time to reflect in the analysis.

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Stem Cell Therapy Market Foraying into Emerging Economies 2017-2025 - Techdadz

Canine Stem Cell Therapy Market is expected to witness a CAGR of 4.2% during the forecast period 2017-2026 – Zebvo

Persistence Market Research (PMR) has published a new research report on canine stem cell therapy. The report has been titled, Canine Stem Cell Therapy Market: Global Industry Analysis 2016 and Forecast 20172026.Veterinary research has been used in regenerative and adult stem cell therapy andhas gained significant traction over the last decade. Canine stem cell therapy products are identified to have gained prominence over the past five years, and according to the aforementioned research report, the market for canine stem cell therapy will expand at a moderate pace over the next few years.

Though all animal stem cells are not approved by FDA, veterinary stem-cell manufacturers and university researchers have been adopting various strategies in order to meet regulatory approvals, and streamline and expedite the review-and-approval process. The vendors in the market are incessantly concentrating on research and development to come up with advanced therapy, in addition to acquiring patents.

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In September 2017, VetStem Biopharma, Inc. received European patent granted to the University of Pittsburgh and VetStem received full license of the patent then. This patent will eventually provide the coverage for the ongoing commercial and product development programs of VetStem and might be also available for licensing to other companies who are rather interested in this field. The other companies operating in the global market for canine stem cell therapy are VETherapy Corporation, Aratana Therapeutics, Inc., Regeneus Ltd, Magellan Stem Cells, Animal Cell Therapies, Inc., and Medrego, among others.

According to the Persistence Market Research report, the globalcanine stem cell therapy marketis expected to witness a CAGR of 4.2% during the forecast period 2017-2026. In 2017, the market was valued at US$ 151.4 Mn and is expected to rise to a valuation of US$ 218.2 Mn by the end of 2026.

Burgeoning Prevalence of Chronic Diseases in Dogs to Benefit Market

Adipose Stem Cells (ASCs) are the most prevalent and in-demand adult stem cells owing to their safety profile, ease of harvest, and use and the ability to distinguish into multiple cell lineages. Most early clinical research is focused on adipose stem cells to treat various chronic diseases such as arthritis, tendonitis, lameness, and atopic dermatitis in dogs. A large area of focus in veterinary medicine is treatment of osteoarthritis in dogs, which becomes more prevalent with age. Globally, more than 20% dogs are suffering from arthritis, which is a common form of canine joint and musculoskeletal disease. Out of those 20%, merely 5% seem to receive the treatment. However, elbow dysplasia in canine registered a prevalence rate of 64%, converting it into an alarming disease condition to be treated on priority. Thereby, with the growing chronic disorders in canine, the demand for stem cell therapy is increasing at a significant pace.

Expensive nature and limited access to canine stem cell therapy has demonstrated to be a chief hindrance forestalling its widespread adoption. The average tier II and tier III veterinary hospitals lack the facilities and expertise to perform stem cell procedures, which necessitates the referral to a specialty vet hospital with expertise veterinarians. A trained veterinary physician charges high treatment cost associated with stem cell therapy for dogs.

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Generally, dog owners have pet insurance that typically covers maximum cost associated with steam cell therapy to treat the initial injury but for the succeeding measures in case of retreatment, the costs are not covered under the pet insurance. The stem cell therapy is thus cost-prohibitive for a large number of pet owners, which highlights a major restraint to the market growth. Stem cell therapy is still in its developmental stage and a positive growth outcome for the market cannot be confirmed yet.

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Canine Stem Cell Therapy Market is expected to witness a CAGR of 4.2% during the forecast period 2017-2026 - Zebvo

Alzheimer’s Disease Insight Report: Current Therapies, Drug Pipeline and Outlook – BioSpace

With one in 10 Americans over 65 currently living with symptomatic Alzheimers disease, you probably know someone affected by this disease. Worldwide, 50 million people live with symptomatic Alzheimers, making it the most common form of dementia. It commonly affects people over 65, but less than 4 percent of the estimated 5.7 million Americans affected have early-onset Alzheimers with symptoms beginning before age 65.

By 2050, nearly 14 million Americans are projected to suffer from this disease. Alzheimers is 6th leading cause of death in the US, making Alzheimers disease a top health concern. Unfortunately, there is no cure, but current medications and management strategies may improve symptoms, prolonging patient independence. In honor of November being Alzheimers Awareness month, we evaluated the current therapies, drugs in the pipeline and disease outlook.

Overview

Alzheimers disease is a degenerative brain disease that typically begins in late middle age or old age. Degeneration of brain cells, called neurons, cause the symptoms of progressive memory loss, impaired thinking, disorientation and mood and personality changes.

Risk factors: The greatest risk factors are old age, having a family history of Alzheimers and carrying a mutation in a certain gene called apolipoprotein E 4 (APOE4). Environmental and lifestyle factors, such as diet and exercise, also contribute to disease development.

The risk of Alzheimers doubles every five years after the age of 65, with nearly 1 in 3 people age 85 or older developing the disease. People with the APOE4 gene variant are thought to have an increased risk for developing late-onset Alzheimers, but thats not a steadfast rule: inheriting the gene variant does not mean the person will definitely get Alzheimers and some Alzheimers patients do not have the APOE4 gene variant.

Causes: Alzheimers develops as a result of a complex interaction between many risk factors, all resulting in neuron damage and death. The buildup of misfolded proteins, such as the tau protein and -amyloid, create the hallmark protein clumps called tangles and plaques seen in Alzheimers brains. While these protein clumps are thought to cause neuron death by blocking nerve cell communication and function, the exact relationship between the protein clump formation and neuron death is still unclear.

The four stages of Alzheimers: Based on the severity of dementia symptoms, Alzheimers can be characterized into four stages: preclinical, mild (early-stage), moderate (middle-stage) and severe (late-stage). The preclinical stage encompasses all the unseen changes in the brain, such as plaque accumulations, happening years before symptoms arise. Mild Alzheimers patients can still function independently, although they begin forgetting familiar words or locations of objects. As the dementia progresses to become moderate, the patient becomes more forgetful, has greater difficulty doing daily tasks and experiences personality and behavioral changes. At this stage, they may still remember significant life events. The moderate disease stage is the longest, often lasting for many years. Finally, severe Alzheimers patients can no longer respond to their environment, carry a conversation and control their movement or bowels. As the disease progresses, patients require an increasing level of care for daily activities.

Life expectancy: The earlier the diagnosis, the longer the life expectancy is: people diagnosed in their 60s to early 70s can live as long as 7 to 10 years, whereas those diagnosed in their 90s only average a 3-year life expectancy. Alzheimers patients live an average of four to eight years after their diagnosis, but can live as long as 20 years post-diagnosis. However, its difficult to link one disease to life expectancy, especially as you age, due to the many variables that influence life expectancy.

Cost: The cost burden of Alzheimers is as high as its prevalence: Alzheimers medications can range from $177 to $400 monthly, adding up to an annual prescription drugs estimated cost of $3,000. It will cost Americans an estimated $277 billion, including $186 billion in Medicare and Medicaid payments, to care for Alzheimers patients by the end of 2018. By 2050, this cost is projected to be more than $1.1 trillion, accounting for over four-fold increases in government spending through Medicare and Medicaid, as well as out-of-pocket expenses. Up to $7.9 trillion in medical and care costs could be saved by diagnosing earlier and more accurately.

Diagnosis Strategies

Although there is no specific test for Alzheimers disease, doctors use a variety of exams, imaging and lab testing to diagnose the disease.

Physical and neurological exams can test reflexes, coordination and memory. Brain imaging is used to rule out other physical abnormalities, such as tumors, stroke or other traumas, that can cause Alzheimers-like symptoms. Imaging can now be used to detect the specific changes that occur in the brains of living Alzheimers patients, not just in post-mortem analysis. Structural imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), are used to rule out other physical injuries as well as assess Alzheimers-related brain shrinkage. Functional imaging, such as functional MRI (fMRI) and positron emission tomography (PET), can measure brain cell function by tracking the cells sugar and oxygen use.

Specific radioactive molecules, called radiotracers, can be used to detect -amyloid plaques via PET imaging. Three radiotracers have been approved by the U.S. Food and Drug Administration (FDA) since 2012: Amyvid (18F-florbetapir), Vizamyl (18F-flutametamol) and Neuraceq (18F-florbetaben).

Genetic testing can reveal if someone has a mutation, such as the APOE4 gene variant, that may increase their risk for developing Alzheimers. However, it is generally not recommended for Alzheimers diagnosis due to the lower accuracy, as many factors contribute to disease development. The exception is early-onset Alzheimers: Anyone with a family history of early Alzheimers can be screened for certain gene mutations, such as amyloid precursor protein (APP), presenilin-1 (PS-1) and presenilin-2 (PS-2).

Developing better diagnostic testing could facilitate earlier diagnoses, possibly leading to better outcomes. Future testing includes more sensitive mental ability exams and measuring key disease-associated proteins, called biomarkers, in the blood or spinal fluid.

Current Therapies

While there is no cure for Alzheimers disease, a handful of drugs have been approved by the FDA and shown to somewhat slow symptom progression. They can be broken down into two categories: cholinesterase inhibitors, which increase the amount of the neurotransmitter acetylcholine in the brain, resulting in more cell-to-cell communication; and NMDA receptor antagonists, which also alter how brain cells communicate.

Cholinesterase inhibitors include Eisais Aricept (donepezil) and Novartis Exelon (rivastigmine), both approved for all stages of Alzheimers, as well as Janssen Pharmaceuticals Razdyne (galantamine), which is approved for mild to moderate Alzheimers. Allerganhas two NMDA receptor antagonist-based drugs, Namenda (memantine) and the combination drug Namzaric (donepezil and memantine), which are both approved for moderate to severe Alzheimers. Antidepressants and anti-anxiety medications are sometimes prescribed as well to help control behavioral symptoms.

Unfortunately, these drugs can cause potentially severe side effects and arent overwhelmingly effective compared to placebo, although they have helped stave off mental decline for a while in some patients. However, the need for more effective drugs is clear.

Drug Pipeline

A variety of targeted therapies are currently being explored through clinical trials, including drugs against the tau protein, which forms distinctive tangles in Alzheimers brains; the -amyloid protein, which forms plaques in the Alzheimers brain; -secretase (BACE), an enzyme that cuts amyloid precursor protein (APP) into -amyloid; and the 5-HT2A serotonin receptor, which is involved in cognition and memory by mediating neurotransmitters, such as acetylcholine and glutamate.

The Alzheimers drug development market includes many large players, including Eli Lillywith six drugs (two in Phase 1, two in Phase 2 and two in Phase 3);Biogen with five drugs (two in Phase 1, one in Phase 2 and two in Phase 3); Roche, in collaboration with Genentech, AC Immune, and MorphoSys, with three drugs (two in Phase 2 and one in Phase 3); Eisai, in collaboration with Biogen, with one drug in Phase 3; and Eisai alone with one drug in Phase 2 (as of September 13, 2019).

As of September 13, 2019, there are over 670 active/recruiting/not yet recruiting clinical trials for Alzheimers listed on clinicaltrials.gov. According to a paper published in July 2019, there were 132 drugs in development for Alzheimers: 28 drugs in 42 Phase 3 trials, 74 drugs in 83 Phase 2 trials, and 30 drugs in 31 Phase 1 trials. The figure and legend below, taken from the July 2019 paper, shows all the drugs in clinical trials for Alzheimers as of February 2019.

UsAgainstAlzheimers released their 2019 Alzheimers Drug Pipeline report also in July 2019, where they focused on 98 late-stage Alzheimers drugs in development that could potentially reach the market in the next 5-10 years: 26 drugs in Phase 3 trials, and 72 drugs in Phase 2 trials. Their report shows that, despite some large Phase 3 failures this year, the Alzheimers pipeline is still robust.

The following analysis of some Alzheimers drugs in the pipeline will briefly discuss how each drug works and where it is in clinical trials. This information was up to date as of September 13, 2019. Any text in italics represents failed or terminated trials.

Phase 1

Biogen is exploring multiple antibody drugs against the -amyloid and tau proteins, including a Phase 1 trial studying the anti-tau antibody BIIB076 in 48 healthy and Alzheimers patients; a Phase 2 trial (TANGO) examining the anti-tau antibody BIIB092 (gosuranemab) in 528 early-stage Alzheimers patients; a Phase 2 trial in collaboration with Eisai studying the anti--amyloid antibody BAN2401 in 800 early-stage Alzheimers patients; and a Phase 3 trial (Clarity AD) studying BAN2401 in 1566 early Alzheimers patients.

Unfortunately, in March 2019, Biogen and its partner Eisai decided to end all studies involving another one of its anti--amyloid antibodies called aducanumab (previously called BIIB037), including their two Phase 3 trials (ENGAGE and EMERGE) each studying 1605 early-stage Alzheimers patients, a Phase 2 trial (EVOLVE) in 500 Alzheimers patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimers, and a Phase 1 trial (PRIME) in 197 very mild (prodromal) or mild Alzheimers patients. The studies were stopped because they did not meet their clinical endpoints of slowing cognitive and functional impairment, not due to any safety concerns of the drug.

Eli Lilly is pursuing two chemical entities, a Tau Morphomer and an O-GlcNAcase Inhibitor, in Phase 1 clinical trials for Alzheimers.

Proclara Biosciencescombined a part of the human immunoglobulin protein with their unique protein technology, called General Amyloid Interaction Motif (GAIM), to create their fusion protein drug NPT088, which targets both -amyloid and tau proteins. Their Phase 1a safety trial showed that intravenous NPT088 is safe and well-tolerated in 40 healthy patients. Data from their Phase 1b dosing trial in Alzheimers patients is expected in 2019.

Cognition Therapeutics drug candidate CT1812 is a small molecule pill that disrupts -amyloid binding to a receptor called sigma-2 on brain cells, which is thought to prevent the proteins toxicity. CT1812 has been or is being studied in six clinical trials, including one recruiting Phase 1 trial with 18 mild to moderate Alzheimers patients, one recruiting Phase 1/2 trial with 21 mild to moderate Alzheimers patients, and one recruiting Phase 2 trial with 120 mild to moderate Alzheimers patients. CT1812 was well-tolerated and penetrated the brain very well in 80 healthy patients and 19 mild to moderate Alzheimers patients with mild to moderate side effects. Although the treated Alzheimers patients had lower levels of Alzheimers-related proteins (such as neurogranin and synaptotagmin-1, markers of synaptic damage) in their cerebrospinal fluid, they didnt show significantly different cognitive functioning compared with the placebo group after 28 days of treatment.

Samus Therapeuticsis developing a positron-emitting molecule, called 124I-PU-AD, that inhibits a certain protein complex called epichaperone complex, which reduced tau proteins in the brain, restored long-term memory and increased survival in preclinical animal models. 124I-PU-AD is also being used as a PET imaging agent to study the epichaperone complex in the brains of Alzheimers patients. They have completed an early Phase 1 trial in 5 Alzheimers and certain cancer patients to evaluate the molecules metabolism. Another Phase 1 study is currently recruiting 24 healthy volunteers to evaluate the safety and tolerance of the drug.

Janssen Research & Development is examining the ability of a radioactive PET imaging agent, called [18F]MNI-1020, to bind to the tau protein in Alzheimers patients. An early Phase 1 trial studied the safety and brain uptake efficacy of a single injection of the imaging agent in 15 Alzheimers and healthy age-matched patients. That study also compared the location of tau (using [18F]MNI-1020) and -amyloid (using Amyvid (florbetapir)) in patients with suspected Alzheimers.

Longeveron collects stem cells from healthy adult donors to create their own Longeveron mesenchymal stem cells (LMSCs), which have been shown to reduce inflammation and promote cell regeneration. Their Phase 1 clinical trial is currently recruiting 30 Alzheimers patients to evaluate the safety and efficacy of LMSCs.

Athira Pharmas small molecule drug NDX-1017 designed to restore lost or build new connections in the brain. Their Phase 1 trial is currently recruiting to evaluate the drugs safety in two parts, with Part A involving up to 56 healthy young and elderly participants and Part B involving 44 healthy, mild cognitive impairment or mild to moderate Alzheimers patients.

Cortexyme, Inc.is developing COR388, a first-in-class bacterial protease inhibitor that targets the bacteria Porphyromonas gingivalis, which is present in Alzheimers patients brains and cerebrospinal fluid and thought to contribute to the disease. Two completed Phase 1 trials have shown that COR388 is safe and well-tolerated in 58 healthy and nine Alzheimers patients. A Phase 2/3 trial is currently enrolling 573 mild to moderate Alzheimers patients to assess the drugs efficacy, safety, and tolerability.

Allergan was pursuing a small molecule drug called AGN-242071 that selectively targeted certain receptors in the brain, called muscarinic receptors, which may treat symptomatic cognitive deficits and behavioral symptoms in Alzheimers.

Unfortunately, Allergan decided to withdraw their Phase 1 trial evaluating the safety and tolerability of the drug prior to patient recruitment in November 2018.

Corium Internationalhas developed a novel delivery method for an approved drug, a once-weekly skin patch (the Corplex Donepezil Transdermal System) that delivers a sustained dose of donepezil. The patchs safety and drug profile were examined in multiple Phase 1 trials, which showed great skin tolerability and comparable dosages between the weekly patch and the currently prescribed daily donepezil pills. Corium is also developing a once-weekly skin patch to deliver memantine

Cognoptix has taken a different approach, developing an eye test called Sapphire II to catch and diagnose Alzheimers much earlier by detecting -amyloid deposits in their eyes. A fluorescent drug that binds to the -amyloid protein (Aftobetin-HCl) is administered to the eye as an ointment and binding is detected with the Sapphire II laser device. Their Phase 1 study determined the optimal dosing of the fluorescent drug in 15 participants and is currently recruiting 10 normal and 20 mild cognitive impairment (MCI) or mild Alzheimers patients for dose testing. If the dosing is optimal, then 30 more MCI and 30 more mild Alzheimers patients will be recruited, totaling 105 participants.

Phase 1/2

Ionis Pharmaceuticalsis collaborating with Biogen to study their antisense oligonucleotide drug IONIS-MAPTRx (also called BIIB080), which may reduce tau protein production and its accumulation in brain cells, in a Phase 1/2 trial in 44 mild Alzheimers patients.

QR Pharma, Inc.s small molecule drug Posiphen inhibits APP, tau and -synuclein (involved with Parkinsons disease) protein synthesis. They are currently recruiting 24 Alzheimers patients for their Phase 1/2 dosage study (DISCOVER).

Following their successful Phase 1 trial (SEAD) in 15 Alzheimers patients, Ausio Pharmaceuticalsbrought their estrogen receptor activating drug S-equol (also called AUS-131) to a Phase 1/2 trial (SEAD2), which is currently recruiting 40 Alzheimers patients to test the drugs tolerability and whether or not it affects cognitive abilities. Activating the estrogen receptors on mitochondria is thought to promote mitochondrial functioning, which could restore the reduced mitochondrial activity seen in Alzheimers patients. Less mitochondrial activity is thought to contribute to -amyloid protein build-up in the brain.

Nature Cell Co. is studying a fat cell-derived mesenchymal stem cell (MSC) therapy called AstroStem in an active Phase 1/2 study involving 21 mild to moderate Alzheimers patients.

Phase 2

Eli Lilly has two ongoing Phase 2 trials studying antibody drugs: one active trial (TRAILBLAZER-ALZ) evaluating the tolerability and efficacy of a humanized anti--amyloid antibody, called donanemab (LY3002813 or N3pG-A MAb), in 266 early symptomatic Alzheimers patients; and another currently recruiting trial evaluating the safety and efficacy of a humanized anti-tau antibody, called zagotenemab (LY3303560), in 285 early symptomatic Alzheimers patients.

Roche, in partnership with AC Immune, is studying crenezumab (RG7412), an anti--amyloid antibody drug that binds to -amyloid similar to Eli Lillys solanezumab. Crenezumab is being investigated in an active Phase 2 trial involving 252 non-symptomatic adults with a family history of Alzheimers who have a particular genetic mutation (autosomal-dominant PSEN1 E280A). Baseline data for 242 of the enrolled patients were presented at the Alzheimers Association International Conference in August 2019. Another not yet recruiting Phase 2 trial is in the works to study the effect of crenezumab on the longitudinal tau burden via PET imaging of 150 patients enrolled in the active Phase 2 trial (NCT01998841).

Crenezumab was being investigated in three Phase 3 trials: CREAD 1 evaluating the drugs safety and efficacy in 813 mild Alzheimers patients; CREAD 2 studying the drugs safety and efficacy in 750 mild Alzheimers patients; and an open-label extension trial (CREAD OLE) examining long-term drug treatment in 149 Alzheimers patients. Unfortunately, in January 2019, Roche discontinued all CREAD trials due to the interim analysis showing crenezumab was unlikely to meet the primary endpoint of improving cognition.

Genentech (a subsidiary of Roche) is partnering with AC Immune to develop the anti-tau antibody drug RO7105705 (also called RG6100 and MTAU9937A), which recognizes tau tangles and is meant to block their spread between cells. An active Phase 2 trial involving 457 prodromal to mild Alzheimers patients is studying the drugs safety and effect on cognitive function.

AbbVies humanized antibody drug ABBV-8E12, which targets the tau protein, is being evaluated for its safety and efficacy in an active Phase 2 trial involving 400 early-stage Alzheimers patients. An extension study to study the drugs long-term safety and tolerability is currently enrolling patients from the Phase 2 study (NCT02880956) by invitation.

Avid Radiopharmaceuticals, a wholly-owned subsidiary of Eli Lilly, is developing the PET imaging agent 18F-AV-1451 (also called Flortaucipir F 18 or F 18 T807), a molecule that binds to the tau protein, allowing researchers to study tau in living patients. There are multiple Phase 2 or Phase 2/3 trials studying the imaging agents safety and efficacy, with five Phase 2 trials currently recruiting or not yet recruiting: one to evaluate the agents safety and tau binding via PET imaging in 250 healthy, Alzheimers, traumatic brain injury and depression patients; one (ADRC proj 1) to compare tau tangles in the brain with cerebrospinal fluid CSF biomarkers and cognitive status in 80 Alzheimers patients; one (DIAN Project, AV ADAD) to study the presence of tau tangles in the brain and cognitive status in 130 adults; one to study the uptake and binding in 80 older HIV-positive adults with and without HIV-associated neurocognitive disorders and HIV-negative age-matched controls; and one (Protocol Z) to study tau and amyloid lesions in the brains of 80 APOE4+ adults with normal cognition or early-stage symptomatic Alzheimers.

Neurotrope Bioscience is developing bryostatin-1, a small molecule that activates protein kinase C (PKC), a protein that is important for learning and memory. This drug stimulates synapse repair and growth, activates -amyloid degrading enzymes and prevents tau tangle formation and neuron death. A Phase 2 trial evaluating the safety and efficacy of bryostatin-1 in 147 moderate to severe Alzheimers patients showed positive results: the lower (20 g) dose improved cognition and the ability to care for oneself. This prompted a second Phase 2 trial to study the drugs safety and efficacy at the lower dose in 108 moderately severe to severe Alzheimers patients.

Unfortunately, Neurotrope announced that the second Phase 2 trial did not show statistically significant improvement in memory, indicating it did not meet its primary endpoint of a change in the Severe Impairment Battery (SIB) test total score from baseline to week 13.

EIP Pharma is pursuing a small molecule called neflamapimod (VX-745) that inhibits an enzyme, called p38 MAPK, found in the neurons that is involved in inflammation and possibly -amyloid toxicity. Neflamapimod previously showed clinical activity in rheumatoid arthritis patients before being licensed to EIP Pharma. They are currently conducting a Phase 2b efficacy study (REVERSE-SD) in 161 participants with mild Alzheimers. A Phase 3 study is scheduled to start in the third quarter of 2020. Another Phase 2 trial is recruiting 40 Alzheimers patients to study neflamapimod on brain inflammation.

Actinogen Medicalis studying a drug called xanamem, which inhibits a cortisol-producing enzyme in the brain, ultimately blocking local production of cortisol, known as the stress hormone. While blood cortisol levels tend to rise with age, its particularly raised in patient with certain diseases, such as Alzheimers. Long-term high cortisol levels can be toxic to brain neurons, so preventing cortisol production in the brain may help slow cognitive decline and -amyloid plaque formation. After assessing xanamems safety and dosing in two Phase 1 trials, a Phase 2 trial (XanADu) assessed the drugs safety and efficacy in 186 early-stage Alzheimers patients.

Boehringer Ingelheims drug BI 425809 is a glycine transport inhibitor designed to regulate signaling in the brain that contributes to cognitive impairment. An active Phase 2 trial is studying the safety and effect on cognition of multiple dosages of the drug in 611 Alzheimers patients.

Neurocentriais developing a dietary supplement called MMFS, which contains a molecule called L-threonic acid magnesium salt (L-TAMS) that increases synapse density in portions of the brain needed for memory and executive functioning, such as the prefrontal cortex and hippocampus. Two previous studies showed improved cognition in mild to moderate Alzheimers patients, prompting the active Phase 2 trial that is recruiting 12 mild Alzheimers patients to examine the drugs safety and effect on cognition.

Alkahestis studying intravenously administered plasma-derived product called GRF6019, which is isolated from human plasma (a component of the blood) that has been shown to enhance neurogenesis and improve learning and memory in animals. Matching donor and patients blood types is not needed because the donor-specific antibodies (called immunoglobulins) are removed. A Phase 2 trial in 40 mild to moderate Alzheimers patients studied the safety and feasibility of GRF6019. Another Phase 2 trial is currently recruiting 20 severe Alzheimers patients to study the safety, tolerability, and cognitive benefits of the drug.

Suven Life Sciences drug SUVN-502 specifically inhibits a certain serotonin receptor (called 5-HT6), which is thought to improve cognition and memory. SUVN-502 in combination with donepezil and memantine was shown to increase the concentration of neurotransmitters, like acetylcholine. An active Phase 2 trial is testing the effect of this triple combination therapy on cognition in 563 moderate Alzheimers patients. An expanded access program is also available for eligible patients to receive the drug without being evaluated for safety and efficacy.

Neurim Pharmaceuticalsis taking a different approach by developing a drug, called piromelatine, that binds to and activates melatonin and serotonin receptors in the brain, promoting sleep and therefore neuroprotective effects. This drug was safe and promoted deeper and more REM sleep in a Phase 2 clinical trial in adults with insomnia. Given the link between sleep and Alzheimers, Neurim decided to study piromelatines effects on cognition in 500 mild Alzheimers patients in an active dose-ranging Phase 2 trial.

Eisai, in collaboration withPurdue Pharma, is studying their orexin receptor antagonist drug lemborexant in a Phase 2 trial involving 62 mild to moderate Alzheimers patients. The orexin receptor is involved in the regulation of sleep. Lemborexant binds to the orexin receptor, preventing orexin from binding, which should decrease wakefulness and promote falling and staying asleep naturally. Sleep, especially at appropriate hours, is troublesome for Alzheimers patients whose circadian rhythms tend to be dysregulated.

Phase 2/3

Novartis has partnered with Amgen and the Banner Alzheimer's Instituteto pursue Novartis drug umibacestat (CNP520), which inhibits BACE1, an enzyme involved in -amyloid production. After a successful Phase 2 trial safety study in 124 healthy elderly patients, there were two Phase 2/3 trials: one (Generation S1) to test the efficacy of CNP520 against an investigational immunotherapy drug (CAD106, a vaccine against a fragment of the -amyloid protein) in 481 non-symptomatic older patients with two copies of the APOE4 gene; and one (Generation S2) to test the drugs effect on cognition and underlying Alzheimers pathology in 1145 non-symptomatic older patients with at least one APOE4 allele and elevated brain -amyloid levels.

Unfortunately, both Phase 2/3 trials were discontinued in July 2019 due to worsening cognitive function seen during interim data analysis. As umibacestat was meant to delay the onset of symptoms, participants in the study will discontinue the investigational treatment and discuss further treatment options with their doctors.

TauRx Therapeutics drug TRx0237 (also called LMTX) is their second-generation tau protein aggregation inhibitor, which aims to both dissolve existing tau tangles and prevent new tangles from forming. Two previous Phase 3 clinical trials studied the safety and efficacy of high doses (150-250 mg/day) and a low dose control (8 mg/day) of the drug in 800 mild and 891 mild to moderate Alzheimers patients. Surprisingly, they found that the low dose was as beneficial as the higher doses, prompting a current Phase 2/3 trial (LUCIDITY) recruiting 375 early Alzheimers patients studying TRx0237 at low doses (8 and 16 mg/day). An expanded access program is also available to provide the drug to patients who have previously participated in a TauRx clinical trial but do not qualify for an ongoing trial.

Axsome Therapeutics is pursuing a treatment for agitation associated with Alzheimers and have been granted fast track status for their drug AXS-05, which combines dextromethorphan and bupropion. Dextromethorphan (called DM and commonly known as an over-the-counter cough suppressant) inhibits serotonin and norepinephrine transporters and the NMDA receptor at high doses. Bupropion increases the bioavailability of dextromethorphan and inhibits norepinephrine and dopamine reuptake. A Phase 2/3 trial (ADVANCE) is currently recruiting 435 Alzheimers patients to study the safety of AXS-05 and its effect on agitation.

Phase 3

Eli Lilly has a Phase 3 anti--amyloid antibody drug called solanezumab (LY2062430), which binds to soluble -amyloid monomers. The primary endpoints of trials involving this drug is to slow memory and cognitive decline. The drug is associated with 11 listed trials, including an active Phase 3 trial (A4) involving 1150 not yet symptomatic adults with evidence of amyloid plaque build-up in their brains, and a currently recruiting Phase 2/3 large collaboration trial (DIAN-TU) comparing solanezumab and gantenerumab in 490 non-symptomatic adults known to have an Alzheimers disease-causing mutation. This collaboration includes Eli Lilly, Roche, Avid Radiopharmaceuticals, Janssen, Alzheimers Association, National Institute on Aging (NIA), Accelerating Medicines Partnership (AMP), and Washington University School of Medicine.

Two Phase 3 trials (EXPEDITION and EXPEDITION 2) were completed previously and involved 1040 Alzheimers patients each. Although there was no difference in cognition between the treated and placebo groups, patients with mild Alzheimers did show slower cognitive decline compared to placebo, prompting further studies.

Unfortunately, the next three Phase 3 trials (EXPEDITION 3, EXPEDITION EXT and EXPEDITION PRO) were terminated due to lack of meeting primary endpoints, including slowing cognitive decline, and insufficient evidence that solanezumab would likely demonstrate a meaningful benefit to patients with prodromal Alzheimers.

Roche is currently investigating gantenerumab, an anti--amyloid antibody drug that binds and neutralizes -amyloid plaques. Gantenerumab, brought back after failing in previous clinical trials, is involved in four Phase 3 trials: two active trials studying the drugs effect on cognitive function in 799 prodromal and 389 mild Alzheimers patients; and two currently recruiting trials studying the drugs effect on cognition in 760 early Alzheimers patients each.

Eisai, in collaboration with Biogen, is studying their small molecule BACE1 inhibitor elenbecestat (also called E2609) in two Phase 3 trials (MISSION AD1 and MISSION AD2) currently recruiting 950 early-stage Alzheimers patients each. Inhibiting BACE1 is thought to interfere with -amyloid production.

Unfortunately, the companies announced that they were discontinuing their MISSION AD1 and AD2 Phase 3 trials on September 13, 2019. The decision was made based on results from a safety review that showed an unfavorable risk-benefit ratio of elenbecestat.

Avid Radiopharmaceuticals and Eli Lilly reported positive results earlier this year from their Phase 3 trial on the tau-binding PET imaging agent flortaucipir F 18 (18F-AV-1451 or Tau imaging agent) in Alzheimers patients. The trial met its two primary endpoints, successfully predicting both the disease-related role of tau in the brain and an Alzheimers diagnosis. PET imaging was performed on 156 end-of-life patients with cognition ranging from normal to dementia, with 67 of these patients being evaluated post-mortem. Flortaucipir could significantly detect Alzheimers-related changes in the brain, including both tau and -amyloid plaque densities. Being able to accurately image and diagnose Alzheimers patients is a critical component in understanding the disease and being able to manage it. There are currently 33 studies listed on clinicaltrials.gov for flortaucipir and Alzheimers.

AZTherapies, Inc. is studying the combination drug ALZT-OP1, which consists of the inhaled drug cromolyn and oral drug ibuprofen, both of which are anti-inflammatory. Inflammation in the brain is thought to trigger neuronal death, which causes progressive brain damage. Cromolyn was also shown to prevent -amyloid aggregation in one study. A Phase 3 trial (COGNITE) is currently studying the effect of this combination drug on cognitive decline in 620 early-stage Alzheimers patients.

ACADIA Pharmaceuticals drug pimavanserin (previously called ACP 103) is a selective serotonin inverse agonist (SSIA), meaning it both binds to serotonin receptor subtype 5-HT2A and blocks serotonin signaling. Following a few Phase 2 trials specifically in Alzheimers patients, there are currently three recruiting Phase 3 trials for a broader range of dementia patients: an efficacy study examining pimavanserins ability to prevent relapse of dementia-related psychosis symptoms in 356 dementia patients, a safety study in 300 patients with neurodegenerative disease, and an open-label extension study examining the drugs long-term safety in 300 patients with neurodegenerative disease who previously participated in another pimavanserin clinical trial by ACADIA.

Intra-Cellular Therapiesis developing lumateperone (ITI-007), a molecule that simultaneously affects serotonin, dopamine and glutamate signaling, which play important roles in multiple mental illnesses. Following a Phase 1b/2 study, they recruited 177 dementia patients, including Alzheimers patients, for a Phase 3 trial studying the safety and efficacy of the drug for reducing agitation.

However, the Phase 3 trial was terminated early due to interim data analysis indicating lumateperones lack of efficacy.

AVANIR Pharmaceuticals drug AVP-786 combines two approved drugs: deuterated dextromethorphan (d6-DM), which has better bioavailability and less side effects than regular DM, and an ultra-low dose of quinidine, which slows the metabolism of d6-DM by inhibiting an enzyme (CYP 2D6) that breaks down d6-DM. AVP-786 is a second-generation version of Nuedexta (formerly AVP-923), which is currently approved to treat pseudobulbar affect (PBA). Currently, there are four recruiting or active Phase 3 trials studying the safety and efficacy of AVP-786 in treating agitation in Alzheimers patients: one recruiting 412 Alzheimers patients with moderate to severe agitation worldwide, one active study involving 522 Alzheimers patients in the US, one completed study involving 410 Alzheimers patients in the US and a long-term extension study recruiting 700 patients who have completed previous clinical trials of AVP-786 by Avanir.

Otsuka Pharmaceutical Co.and Lundbeck are collaborating to develop brexpiprazole (brand name Rexulti) for treating agitation and behavioral symptoms in Alzheimers patients. Rexulti, which binds to and activates a particular dopamine receptor (D2), is currently FDA approved to treat schizophrenia and as an add-on treatment for major depression disorder. Two Phase 3 trials examining brexpiprazole at either fixed or flexible doses in a total of 703 Alzheimers patients showed reduced agitation compared to the placebo. They are currently recruiting for three Phase 3 trials: one evaluating the safety, efficacy, and tolerability in 225 Alzheimers patients with dementia-associated agitation in the US; one studying long-term treatment in 157 Alzheimers patients with dementia-associated agitation in Japan; and a 12-week extension study for 250 Alzheimers patients with dementia-associated agitation who were previously enrolled in other Otsuka trials studying brexpiprazole. They are also recruiting for a Phase 2/3 study in 407 Alzheimers patients with dementia-associated agitation in Japan.

Merck Sharp & Dohme Corp., a subsidiary of Merck, is studying their FDA approved drug suvorexant (previously called MK-4305, brand name Belsomra) to treat insomnia in Alzheimers patients. Currently approved for insomnia patients, the small molecule drug works by inhibiting the orexin receptor in the signaling system involved in wakefulness. Their Phase 3 trial studying suvorexants safety and efficacy at improving sleep in 285 Alzheimers patients and patients with insomnia concluded in October 2018, but results have not been posted yet.

Preclinical Candidates

A few companies are investigating drugs in the preclinical laboratory setting, hoping to gather promising data to bring their drugs to clinical trials.

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Alzheimer's Disease Insight Report: Current Therapies, Drug Pipeline and Outlook - BioSpace

Partner Therapeutics Receives Orphan Drug Designation for Leukine (sargramostim) – Odessa American

LEXINGTON, Mass., Sept. 19, 2019 /PRNewswire/ -- Partner Therapeutics, Inc. (PTx), a commercial biotechnology company, announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to Leukine (sargramostim), a yeast-derived recombinant human granulocyte-macrophage colony stimulating factor (rhuGM-CSF), for the potential treatment of Stage IIb-IV melanoma.

Melanoma is the most aggressive form of skin cancer and rates of melanoma have been rising for the past 30 years. The American Cancer Society estimates 96,480 new melanoma cases will be diagnosed in the US and 7,230 people will die from the disease in 2019. The FDA grants orphan drug designation to promote the development of promising treatments for conditions that affect 200,000 or fewer U.S. patients annually. If a product holding Orphan Drug Designation receives the first FDA approval for the disease in which it has such designation the company qualifies for, among other things, seven years of market exclusivity following marketing approval.

The Eastern Cooperative Oncology Group (ECOG) previously reported results of Study 1608, a Phase II study in which patients with advanced stage melanoma received a combination of sargramostim and ipilimumab or ipilimumab alone1. Among 245 patients, the addition of sargramostim led to longer survival (median 17.5 vs 12.7 months). The most common Grade 3-5 toxicities in patients treated with sargramostim and ipilimumab were diarrhea (12.7%) and rash (9.3%) and occurred at similar rate in patients receiving ipilimumab alone. Overall, severe toxicities occurred less frequently in patients treated with sargramostim plus ipilimumab vs ipilimumab alone (44.9% vs 58.3%, Grade 3-5); the most notable reductions were in gastrointestinal and pulmonary toxicities. The results of this study led to initiation of a larger Phase 2/3 study (ECOG 6141) evaluating sargramostim in combination with ipilimumab and nivolumab as initial treatment of advanced or metastatic melanoma. This ongoing study is being conducted by ECOG with support from the National Cancer Institute.2

"Leukine's role as an immunomodulator was not the initial focus when it was first discovered decades ago. As we learn more about the immunologic effects of GM-CSF on antitumor immunity, we believe there is potential to develop Leukine to help more patients benefit from treatment with checkpoint inhibitors in melanoma and other difficult to treat cancers," said Bob Mulroy, PTx's CEO. "This orphan designation is an important step in the development of Leukine. We are pleased FDA has programs such as Orphan Drug Designation to support research in rare diseases."

Leukine was initially approved in the United States in 1991 and has five hematologic oncologic indications. Leukine is currently not approved for the treatment of melanoma. The approval of an orphan drug designation request does not alter the standard regulatory requirements and processes for obtaining marketing approval of an investigational drug. Sponsors must establish safety and efficacy of a compound in the treatment of a disease through adequate and well-controlled studies.

Please see full Prescribing Information for LEUKINE at http://www.leukine.com

About Leukine (sargramostim)

Leukine is a yeast-derived recombinant humanized granulocyte-macrophage colony stimulating factor (rhuGM-CSF) and the only FDA approved GM-CSF. GM-CSF is an important leukocyte growth factor known to play a key role in hematopoiesis, effecting the growth and maturation of multiple cell lineages as well as the functional activities of these cells in antigen presentation and cell mediated immunity3.

Important Safety Information for LEUKINE (sargramostim)

Contraindications

LEUKINE is contraindicated in patients with known hypersensitivity to human granulocyte-macrophage colony stimulating factor such as sargramostim (GM-CSF), yeast-derived products, or any component of LEUKINE.

Warnings and Precautions

Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with LEUKINE. If any serious allergic or anaphylactic reaction occurs, immediately discontinue LEUKINE therapy and institute medical management. Permanently discontinue LEUKINE in patients with serious allergic reactions.LEUKINE can cause infusion-related reactions, including respiratory distress, hypoxia, flushing, hypotension, syncope and/or tachycardia. Observe closely during infusion, particularly in patients with preexisting lung disease, as dose adjustment or discontinuation may be required.Do not administer LEUKINE simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy.Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE administration. LEUKINE should be used with caution and monitored in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure.Supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. Use LEUKINE with caution in patients with preexisting cardiac disease.If ANC > 20,000 cells/mm3 or if WBC counts > 50,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. Twice weekly monitoring of CBC with differential should be performed.LEUKINE therapy should be discontinued if disease progression is detected during treatment.Treatment with LEUKINE may induce neutralizing anti-drug antibodies. Use LEUKINE for the shortest duration required.Liquid solutions containing benzyl alcohol (including LEUKINE Injection) or LEUKINE for Injection reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates and low birth weight infants.Concomitant use of drugs that can potentiate the myeloproliferative effects of LEUKINE should be avoided.

Adverse Reactions

Adverse events occurring in >10% of patients receiving LEUKINE in controlled clinical trials and reported in a higher frequency than placebo are:

In Autologous bone marrow transplantation (BMT) patientsasthenia, malaise, diarrhea, rash, peripheral edema, urinary tract disorderIn Allogeneic BMT patientsabdominal pain, chills, chest pain, diarrhea, nausea, vomiting, hematemesis, dysphagia, GI hemorrhage, pruritus, bone pain, arthralgia, eye hemorrhage, hypertension, tachycardia, bilirubinemia, hyperglycemia, increase creatinine, hypomagnesemia, edema, pharyngitis, epistaxis, dyspnea, insomnia, anxiety, high glucose, low albuminIn AML patientsfever, weight loss, nausea, vomiting, anorexia, skin reactions, metabolic laboratory abnormalities, edema

Please see full Prescribing Information for LEUKINE at http://www.leukine.com

Indications and Usage

LEUKINE (sargramostim) is a leukocyte growth factor indicated for the following uses:

LEUKINE is indicated to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).LEUKINE is indicated in adult patients with cancer undergoing autologous hematopoietic stem cell transplantation for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.LEUKINE is indicated for the acceleration of myeloid reconstitution following autologous peripheral blood progenitor cell (PBPC) or bone marrow transplantation in adult and pediatric patients 2 years of age and older with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL).LEUKINE is indicated for the acceleration of myeloid reconstitution in adult and pediatric patients 2 years of age and older undergoing allogeneic bone marrow transplantation from HLA-matched related donors.LEUKINE is indicated for the treatment of adult and pediatric patients 2 years and older who have undergone allogeneic or autologous bone marrow transplantation in whom neutrophil recovery is delayed or failed.LEUKINE is indicated to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]).

About Partner Therapeutics, Inc.:

PTx is an integrated commercial-stage biotech company focused on the development and commercialization of therapeutics that improve health outcomes in the treatment of cancer. PTx's development focus spans the entire range of cancer therapy from primary treatments to supportive care. The company believes in delivering great products with the purpose of creating the best possible outcomes for patients and their families.

References: 1. Hodi FS, et al. Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma A Randomized Clinical Trial. JAMA. 2014;312(17):1744-1753

2. National Cancer Institute. Nivolumab and ipilimumab with or without sargramostim in treating patients with stage III-IV melanoma that cannot be removed by surgery. Available at: https://clinicaltrials.gov/ct2/show/NCT02339571. NLM identifier: NCT02339571. Accessed August 26, 2019

3. Armitage JO. Blood. 1998;92(12):4491-4508

View original content to download multimedia: http://www.prnewswire.com/news-releases/partner-therapeutics-receives-orphan-drug-designation-for-leukine-sargramostim-300921156.html

SOURCE Partner Therapeutics, Inc.

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Partner Therapeutics Receives Orphan Drug Designation for Leukine (sargramostim) - Odessa American

Stem Cells Market Predicted to Surpass US$167.33 Bn By 2025 – TheSlapClap

In theglobal stem cells marketa sizeable proportion of companies are trying to garner investments from organizations based overseas. This is one of the strategies leveraged by them to grow their market share. Further, they are also forging partnerships with pharmaceutical organizations to up revenues.

In addition, companies in the global stem cells market are pouring money into expansion through multidisciplinary and multi-sector collaboration for large scale production of high quality pluripotent and differentiated cells. The market, at present, is characterized by a diverse product portfolio, which is expected to up competition, and eventually growth in the market.

Some of the key players operating in the global stem cells market are STEMCELL Technologies Inc., Astellas Pharma Inc., Cellular Engineering Technologies Inc., BioTime Inc., Takara Bio Inc., U.S. Stem Cell, Inc., BrainStorm Cell Therapeutics Inc., Cytori Therapeutics, Inc., Osiris Therapeutics, Inc., and Caladrius Biosciences, Inc.

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As per a report by Transparency Market Research, the global market for stem cells is expected to register a healthy CAGR of 13.8% during the period from 2017 to 2025 to become worth US$270.5 bn by 2025.

Depending upon the type of products, the global stem cell market can be divided into adult stem cells, human embryonic stem cells, induced pluripotent stem cells, etc. Of them, the segment of adult stem cells accounts for a leading share in the market. This is because of their ability to generate trillions of specialized cells which may lower the risks of rejection and repair tissue damage.

This review is based on the findings of a TMR report, titled, Stem Cells Market (Product Adult Stem Cell, Human Embryonic Stem Cell, and Induced Pluripotent Stem; Sources Autologous and Allogeneic; Application Regenerative Medicine and Drug Discovery and Development; End Users Therapeutic Companies, Cell and Tissues Banks, Tools and Reagent Companies, and Service Companies) Global Industry Analysis, Size, Share, Volume, Growth, Trends, and Forecast 20172025.

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Stem Cells Market Predicted to Surpass US$167.33 Bn By 2025 - TheSlapClap

Story of life: Seven wonders of biological research – The Irish Times

Everyone has heard of the seven wonders of the ancient world. Today I present my verdict on seven wonder discoveries in biological research, listed in rough chronological order.

Wonder 1: Cell TheoryCell theory, formulated in 1839, made three assertions: (a) All organisms are composed of basic units called cells; (b) The cell is the basic unit of structure and organisation in all living organisms; (c) New cells arise only from pre-existing cells.

Cell theory rationalised basic biology and contradicted the common notion that life can arise spontaneously from non-living matter.

Wonder 2: The Theory of Evolution Through Natural Selection.This is the most significant-ever insight into biology and was jointly proposed in 1858 by Charles Darwin (1809-1882) and Alfred Russell Wallace (1823-1913). It was already known that life on earth changes over long time periods. The theory of evolution explained the mechanism underpinning these changes natural selection. This theory draws all biology together into one unified framework. In its absence, biology would be reduced to a vast catalogue of unrelated observations.

Wonder 3: The Chemistry of LifeLife, unlike mechanical machines, works close to room temperature and without the assistance of significant temperature or pressure gradients. How then do cells grow, divide and create local order in a world that otherwise moves towards increasing disorder? This question was answered by biochemistry the chemistry of life.

A living cell is the end product of co-ordinated reactions between its innumerable chemical constituents metabolism. These reactions must proceed fast enough at room temperature to sustain life, and this is enabled by protein catalysts called enzymes, discovered in the 1800s. Cell metabolism is driven by energy, ultimately supplied by sunlight.

Wonder 4: Antibiotics and VaccinationsAntibiotics, discovered in 1928, are used to kill pathogenic microbes, and vaccination to provide immunity against disease has been in widespread use since 1900. Vaccination has eliminated many deadly diseases, including smallpox and polio.

Average life expectancy in 1900 was 50 years; today that figure is 82 years. Antibiotics and immunisation are one significant cause of this improvement. If we lost antibiotics and vaccinations today, life expectancy would gradually revert to 50-60 years.

Wonder 5: Discovering the Structure of DNAFaithful inheritance of parental characteristics by offspring is essential for biological evolution. The nature of the cells hereditary material was identified as nucleic acid (DNA) in 1944. In 1953, James Watson (born in 1928) and Francis Crick (1916-2004) made the greatest biological discovery of the 20th century when they solved the structure of DNA, a discovery that also indicated how DNA replicates and transmits genetic information from generation to generation.

DNA is a long molecule made of four sub-units A,T,G,C. Genetic information is encoded in the linear sequence (genes) of these subunits, dictating the structure/activity of all cell proteins, including all enzymes, thereby controlling the activities of the cell. Understanding DNA unlocked the secret of the molecular logic of life.

Wonder 6: CloningEvery animal body cell, including cells of the early embryo, contains a full set of the animals genes. Therefore, inducing any body cell into developing as embryonic cells develop should produce a genetic copy of the animal a clone. In 1996 Dolly the sheep was cloned in this manner.

Cloning offers many huge potential benefits, eg cloning animals, genetically modified to secrete a human hormone, to produce herds secreting large quantities of the hormone for use by patients deficient in the hormone. Cloning could also rebuild endangered animal populations or revive extinct animals.

Wonder 7: Induced Pluripotent Stem CellsThe human body is composed of over 200 tissues/organs skin, liver etc. Each tissue cell is differentiated to do a particular job. But all tissue cells develop from embryonic undifferentiated pluripotent stem cells.

In 2006 Shinya Yamanaka discovered how to transform differentiated body cells into pluripotent stem cells. These induced pluripotent stem cells (IPSC) can be coaxed to develop into specific adult tissues.

IPSCs have huge potential in many areas, eg regenerative medicine. New organs could be grown from patients own IPSCs to replace failing organs and without fear of immune rejection.

IPSCs are extremely useful for many research purposes, eg testing new drugs, and can substitute for stem cells extracted from human embryos, thereby avoiding ethical problems.

William Reville is an emeritus professor of biochemistry at UCC

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Story of life: Seven wonders of biological research - The Irish Times

Cell Harvester Market Share, Growth by Top Company, Region, Applications, Drivers, Trends & Forecast to 2025 – Market Forecast

Cell harvester is a device in which cells are regenerate, and that regenerative cells further used in transplantation and repair the affected organs. Biopharmaceuticals industry and related downstream process are mainly dependent on cell harvesting techniques. Cell harvester plays an important role in treating various types of diseases such as cancers, immune-deficiency related diseases, blood-related disorder, etc. In some Burn cases, cell harvesting is also beneficial to the victim in the form of grafting new skin cells. Several Bio-Pharma companies are trying to manufacture regenerating medicine by focusing regenerative myocardial tissue ability by cell grafting method in which adult stem cell injected into the patient. Cell harvester can also be used in eye disease treatment. Some companies are also manufacturing such devices which consist passive flexible drilling unit as well as cell harvesting system that are used in bone marrow transplantation. Cell harvesters market is growing tremendously due to the broad spectrum of cell harvester usage. Biopharmaceutical Company's attractiveness towards regenerative medicine is the reason for the rapid increment of the cell harvester market growth.

Cell Harvester market: Drivers and Restraint

Increasing incidence and prevalence of blood cancer, blood-related disease, increasing organ transplantation procedure rate, improving healthcare expenditure are considered as the driver for the cell harvester market. Multipurpose use of cell harvester also drives the growth of cell harvester market. The complexity of the procedure, less of awareness and lack of reimbursement, this factor may restrain the growth of cell harvester market.

Cell harvester market: Segmentation

The global market for Cell Harvester segmented by product type, modality, end user, and geography:

Based on modality, Automated Manual Auto-trap

Based on application Cell Proliferation Assays Mixed Lymphocyte Culture (MLC) Assays Receptor-binding Assays Single-Stranded Template DNA Harvesting

Browse more detail information about this report visit at at https://www.transparencymarketresearch.com/cell-harvester-market.html

Based on end-user Research Centers Academics Institutes Diagnostic Labs Hospitals

Segmented by geography North America Latin America Europe Asia Pacific The Middle East and Africa

Cell Harvester Market: Overview

Cell harvesting systems market shows promising growth owing to equipment efficacy and accuracy during cells harvest. By application type, Cell Proliferation Assays is anticipated to hold the major share in the cell harvesting systems market owing to less process error, safe and simple procedure and fewer side effects.

By product modality, cell harvester segmented into three categories whereas, automated cell harvester devices are widely used in worldwide.

Based on the end user, cell harvester can be used by several end user such as research centers. Hospital ,Academic Institutes, etc., research center, share large percentage as end user followed by the hospital.

Cell Harvester Market: Region-wise Outlook

By regional, global Cell Harvester market is segmented into five key regions viz. North America, Latin America, Europe, Asia-Pacific, and Middle East & Africa. Asia Pacific dominates the global cell harvester market followed by Europe and will continue to dominate the global Cell Harvester market attributed to holding high potential and rising growth in terms of wide acceptance of cell harvester technology. Furthermore, increasing rate of procedures and improving healthcare expenditure also expected to boost the global cell harvester market over the forecasted period. North America is expecting emerging market for the cell harvester market.

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Cell Harvester Market: Key Market Participants

Key players of the cell harvesting systems market are PerkinElmer Inc. Tomtec, Bertin Technologies, TERUMO BCT, INC., hynoDent AG, Avita Medical, Argos Technologies, Inc., SP Scienceware, Teleflex Incorporated., Arthrex, Inc., Thomas Scientific, BRAND GMBH

The report offers a comprehensive evaluation of the market. It does so via in-depth qualitative insights, historical data, and verifiable projections about market size. The projections featured in the report have been derived using proven research methodologies and assumptions. By doing so, the research report serves as a repository of analysis and information for every facet of the market, including but not limited to: Regional markets, technology, types, and applications.

The study is a source of reliable data on: Market segments and sub-segments Market trends and dynamics Supply and demand Market size Current trends/opportunities/challenges Competitive landscape Technological breakthroughs Value chain and stakeholder analysis

The regional analysis covers: North America (U.S. and Canada) Latin America (Mexico, Brazil, Peru, Chile, and others) Western Europe (Germany, U.K., France, Spain, Italy, Nordic countries, Belgium, Netherlands, and Luxembourg) Eastern Europe (Poland and Russia) Asia Pacific (China, India, Japan, ASEAN, Australia, and New Zealand) Middle East and Africa (GCC, Southern Africa, and North Africa)

The report has been compiled through extensive primary research (through interviews, surveys, and observations of seasoned analysts) and secondary research (which entails reputable paid sources, trade journals, and industry body databases). The report also features a complete qualitative and quantitative assessment by analyzing data gathered from industry analysts and market participants across key points in the industrys value chain.

A separate analysis of prevailing trends in the parent market, macro- and micro-economic indicators, and regulations and mandates is included under the purview of the study. By doing so, the report projects the attractiveness of each major segment over the forecast period.

Highlights of the report: A complete backdrop analysis, which includes an assessment of the parent market Important changes in market dynamics Market segmentation up to the second or third level Historical, current, and projected size of the market from the standpoint of both value and volume Reporting and evaluation of recent industry developments Market shares and strategies of key players Emerging niche segments and regional markets An objective assessment of the trajectory of the market Recommendations to companies for strengthening their foothold in the market

Note:Although care has been taken to maintain the highest levels of accuracy in TMRs reports, recent market/vendor-specific changes may take time to reflect in the analysis.

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Cell Harvester Market Share, Growth by Top Company, Region, Applications, Drivers, Trends & Forecast to 2025 - Market Forecast

This Womans Toothache Medication Actually Turned Her Blood Blue – Prevention.com

The New England Journal of Medicine 2019.

When you take medication, you expect that it will work to make you feel better. What you dont expect is that it will turn you blue. Unfortunately, thats what happened to one woman in Rhode Islandand she ended up in a case report.

The 25-year-old woman, who was not publicly identified, went to an emergency room in Providence, Rhode Island, with generalized weakness, fatigue, shortness of breath, according to The New England Journal of Medicine. She was also concerned about the fact that she was, you know, turning blue.

After evaluating her, the womans doctors determined that she was turning blue thanks to a numbing agent she had used. She reported having used large amounts of topical benzocaine the night before for a toothache, the case report authors wrote.

The woman was diagnosed with methemoglobinemia, a blood disorder where an abnormal amount of methemoglobin is produced. Methemoglobin is a form of hemoglobin, the protein in red blood cells that carries and distributes oxygen to the body, according to the U.S. National Library of Medicine. However, it is a dark pigment that causes blood to appear very dark in color, says Jamie Alan, PhD, an assistant professor of pharmacology and toxicology at Michigan State University.

There is normally a small percentage of this compound in the red blood cells, however it is kept very low, she explains. But certain compounds like benzocaine can accelerate the formation of methemoglobin. The result? Hemoglobin cannot successfully release critical oxygen to the tissues, so the body turns blue.

Methemoglobinemia is usually either inherited from your family or caused by exposure to certain chemicals, medicines, or foods, the U.S. National Library of Medicine says. Those can include anesthetics like benzocaine, nitrobenzene (which is used in some drugs, pesticides, and dyes), certain antibiotics like dapsone and chloroquine, and nitrates (which are used as additives to keep meat from spoiling).

Benzocaine and similar compounds used to be in infant and childrens teething gels, but it was taken out of those products because of this exact thing, Alan says.

A bluish tint to the skin is a major symptom of methemoglobinemia, but a person can also have a headache, giddiness, altered mental state, fatigue, shortness of breath, and lack of energy.

Methemoglobinemia is very harmful, Alan says. The problem is that methemoglobinemia reduces the ability of your red blood cells to carry oxygen. This can lead to heart attack, stroke, organ damage, and death, she adds.

A medication called methylene blue is used to treat severe cases of methemoglobinemia and ascorbic acid (aka vitamin C) can also be used to reduce the amount of methemoglobin in a patients blood, the U.S. National Library of Medicine says. Undergoing hyperbaric oxygen therapy, a blood cell transfusion, and exchange transfusions (where a persons blood is removed and replaced) can also be helpful.

People dont usually need treatment for mild cases of methemoglobinemia, thoughthey should just avoid the medication or chemical that caused their condition in the first place. The half life of methemoglobin is 55 minutes, meaning the condition will usually reverse in hours, Alan says. In the meantime, the patient needs supportive care with oxygen.

If you suspect youve developed methemoglobinemia, see a doctor immediately.

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This Womans Toothache Medication Actually Turned Her Blood Blue - Prevention.com

SCD: Hypertension Tablet May Prevent Vaso-Occlusive Crisis, Study Says – Sickle Cell Anemia News

A medication used to treat high blood pressure, called valsartan, may help decrease the stickiness of red blood cells and reduce the risk of vaso-occlusive crisis in people with sickle cell disease (SCD), a research study suggests.

The study, Valsartan impedes epinephrine-induced ICAM-4 activation on normal, sickle cell trait and sickle cell disease red blood cells, was published in the journal PLOS One.

SCD is characterized by the production of abnormal hemoglobin proteins, resulting in red blood cells (RBCs) that are stickier and more prone to aggregate together and to blood vessel walls. When such RBC clumps are formed, they can cause painful blockage of blood vessels, a condition that is called vaso-occlusive crisis(VOC).

This blockage process is in part due to abnormally high activation of cell surface proteins, including the intercellular adhesion molecule-4 (or ICAM-4) that mediates RBC clumps binding to blood vessel walls.

Previous studies have suggested that the hormone epinephrine (commonly known as adrenaline) can also contribute to the increased production of ICAM-4 molecules at the surface of RBCs in response to physical stress.

This research led scientists from the University of Connecticut to explore whether using an inhibitor to block the signals of epinephrine could be beneficial in preventing vaso-occlusive episodes. They evaluated the impact of valsartan, an approved oral therapy to reduce blood pressure and treat congestive heart failure, which is sold with the brand name Diovan by Novartis.

The study enrolled five healthy volunteers, three patients with sickle cell trait (SCT, who have both normal and mutated hemoglobin variants), and six patients with diagnosed SCD, who provided blood samples for analysis.

The team used a technique called atomic force microscopy to collect information on the stickiness status of blood cells. This approach can specifically determine the binding force between ICAM-4 at the surface of RBCs to the blood vessel walls.

The researchers found that the binding frequency of ICAM-4 to vessel walls increased in the presence of epinephrine in all three groups. We observed that epinephrine significantly increased the surface percentage of active ICAM-4 receptors, they wrote.

Treatment with valsartan significantly decreased ICAM-4-binding to 10.41% from 17% in RBC samples of healthy volunteers. Similar results were seen in both SCT and SCD samples, with valsartan lowering epinephrine-induced levels of ICAM-4 to 6.87% from 17.11% in SCT blood samples, and to 10.07% from 20.58% in SCD samples.

Supported by these findings, the researchers said that administration of valsartan could mitigate the vaso-occlusive consequences of SCD and may open new avenues for the development of novel therapeutic targets.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.

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SCD: Hypertension Tablet May Prevent Vaso-Occlusive Crisis, Study Says - Sickle Cell Anemia News