Category Archives: Gene Therapy Clinics

4 Barriers To Cell And Gene Therapy Development For Rare …

By Ben Solaski and Perry Yin, Ph.D., PA Consulting

Rare diseases, as defined by the Orphan Drug Act, are diseases that affect less than 200,000 people. Given that approximately 80 percent of the 7,000 known rare diseases are caused by a single-gene defect,1 there has been increased research in the development of cell and gene therapies to treat rare diseases.

However, a number of challenges hinder these efforts, including pricing and reimbursement, the high cost of bringing these drugs to market, unique manufacturing and supply chain challenges, and our current limited understanding of disease pathology and progression. While these challenges may seem common across other drug markets, in the case of rare diseases, these challenges are exacerbated by limited patient populations. In this article, we look at the four challenges in greater depth and explore potential responses to help pharma companies be successful in bringing these products to market.

1. Making Commercialization Viable By Tackling High Costs Together

Given the small patient population, and the high price of drugs aimed at rare diseases, how can we ensure the long-term commercial viability of these drugs? This challenge can be explored from two points of view - how health authorities can promote scientific advancements while also protecting investments in rare disease development and how pharma can collaborate with payers to find better pricing solutions to reduce hurdles for patients to receive treatment.

Over the years, the FDA has taken concrete steps to incentivize the industry to develop drugs for rare diseases. In 2017, the FDA sought to eliminate the backlog for orphan drug requests by responding to future requests within 90 days.2 More recently, the FDA released a Draft Guidance on Human Gene Therapy for Rare Diseases, which pledges that the FDA will be involved with drug companies earlier in the development process. This will not only help streamline development by helping limit the number of preclinical or other preparatory studies but will also lower development costs and increase speed to market.3 But is this enough? There is ongoing debate in the pharma industry that the FDA needs to go even further. For example, while the agency already grants a longer exclusivity period for orphan drugs, this seven-year period is usually outlasted by the 20-year protection offered by patents.4 To sweeten the deal, the FDA may need to consider offering increased protection by expanding this exclusivity period. This would make these drugs more commercially viable, better ensuring capture of initial and ongoing investment in small markets or providing an option for improved pricing scenarios.

On the payer front, as the healthcare industry shifts toward value-based healthcare, orphan drugs and cell and gene therapies that have been prohibitively expensive will be prime candidates for emerging pricing models derived from measuring health outcomes against the cost of treatment. One great example is Novartis CAR-T treatment, Kymriah. For this treatment, Novartis only receives payment if the patient shows significant improvement within a month; otherwise, Novartis bears the cost. The use of value-based pricing models for cell and gene therapies would ease the amount of risk that payers take on when reimbursing these treatments, while also increasing the likelihood that patients will have access to these drugs.

With higher rates of approvals, longer periods of exclusivity, and greater utilization of value-based pricing, cell and gene therapies for rare diseases will have a greater chance of both reaching patients and being commercially successful.

2. Improving Clinical Development: A New Age In Clinical Trial Design And Recruitment

Companies developing cell and gene therapies for rare diseases are confronted with many of the same challenges faced by more traditional drugs; however, these challenges are amplified. These challenges include small patient populations, high mortality rates, and lack of disease state understanding, making it difficult to set clinical endpoints.

Seeking to address this, the FDAs Draft Guidance on Human Gene Therapy for Rare Diseases focuses on new clinical trial designs. What will these trials of the future look like? Gone are the days of three-phase randomized, controlled clinical trials. New age trials for rare diseases will be shorter, combining phases to show both safety and efficacy. Later stage trials will be replaced with rollover studies to see longer-term effects of treatment. Control groups will be replaced with natural history studies to illustrate what happens when patient groups go untreated. Natural history studies will also help to identify surrogate endpoints that can serve as early indicators of future outcomes to help expedite trials.

While these trial designs will help improve the process, there is still the inherent issue of recruiting from such small and geographically diverse patient populations. To ease this, there will be increasing demand for accurate patient registries that include relevant information about potential biomarkers for treatment. GSKs partnership with 23andMe is a good example of how this would work. Genetic data is captured through commercial genetic testing, then used to drive novel drug development and identify patients with specific rare diseases for trial recruitment. Pharma and CROs will also leverage increased use of digital technology to execute remote or highly fragmented multisite trials, making trial participation easier for patients.

Streamlining the clinical trial pathways for gene therapy and rare diseases, as well as reducing the burden on the patient, allows pharma companies to accelerate products to market.

3. Overcoming The Challenges Of Manufacturing And Supply Chain By Partnering With Contract Manufacturer Organizations

There are two major manufacturing challenges. The first is addressing the need for new infrastructure such as advanced supply chains, since the effective handling of these treatments will often require a high degree of customization for the patient (e.g., CAR T cell therapies). The other challenge lies with rare disease and cell and gene therapy products, whose manufacturing requires specialized skills where there is little room for error. As such, organizations will need to decide if they will build the capability or leverage contract organizations.

To address these challenges, in the short term, it is essential that companies have robust chain of custody protocols and supporting technologies to track and monitor these drug products from factory to patient. This ensures the correct patient is getting the therapy that was specifically designed for them, and that the conditions in transit do not damage the drug product. Longer term, the rise of a larger number of small manufacturing sites spread across the country is expected. Smaller manufacturing sites distributed in key geographic regions reduce shipping time, thus reducing the possibility for delays. Taking this one step further, imagine a world where manufacturing sites do not exist, and hospitals or clinics will have the capability and infrastructure to perform specialized manufacturing on-site.

How can pharma get to a commercial scale to support successful complex manufacturing requiring specialized skills? One solution is to outsource manufacturing to contract manufacturing organizations (CMOs) that specialize in gene therapies and rare diseases, similar to the way that clinical research has increasingly relied on contract research organizations (CROs). CMOs manufacture the product as a service and use their expertise to produce high-quality product at a reduced cost.

By using specialists to support the manufacturing process and technology to monitor and localize the supply chain, companies can reduce the risks involved in getting high-quality products to patients.

4. Increasing Our Understanding Of Disease States: The Rise Of Natural History Studies And Companion Diagnostics

Currently, there is a lack of understanding of rare diseases, especially around diseases variations and subtypes. This creates the challenge of how to better identify these variations to develop treatments that are then targeted at a specific disease subtype.

Pharma companies will need to spend more time and effort understanding disease states. For rare diseases, natural history studies are critical to provide insight that could help to drive early development, and even serve as a control group in single-arm studies if randomized, concurrent controlled trials are not feasible.5 Natural history studies may also help identify biomarkers that will help tailor these cell and gene therapies to be more personalized to specific subgroups of patients, allowing companies to be more focused in the development process.

Furthermore, to get the best results from treatment, the patient population that would benefit most from treatment needs to be identified. Thus, the industry will likely see an increase in products entering the market that include a companion diagnostic. Both the FDA and payers have an incentive to require drug manufacturers to develop these diagnostics in parallel with drug projects to ensure the best patient outcomes possible. Advancements in next-generation sequencing techniques will make identifying these subgroups easier and more accurate, potentially leading to a one size fits all genetic test that could be applied to all rare disease products.

Genetic tests, combined with an increase in understanding of natural history and disease biomarkers, will ensure the correct patients are receiving the therapies being developed.


Cell and gene therapies for the rare disease space are still emerging and will continue to face new challenges around development, the evolving regulation landscape, pricing and reimbursement, and manufacturing. Despite these challenges, the first products have already reached the market. New approaches and solutions, such as some of those outlined in this article, will go a long way to meeting these challenges and reducing the barriers to entry, allowing pharma to bring these products to market more quickly and affordably.


About The Authors:

Ben Solaski is a life sciences expert at PA Consulting. With his training as a biomedical engineer, he has extensive experience with the development of gene editing technologies and an understanding of their potential to disrupt the industry. Contact him on LinkedIn at

Perry Yin, Ph.D., is a life sciences expert at PA Consulting, where he leads the Cell and Gene Therapy group. He has experience developing technologies like CRISPR and stem cell-based therapies from concept to animal testing for both cancer and regenerative medicine applications. Contact him on LinkedIn at

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4 Barriers To Cell And Gene Therapy Development For Rare ...

Gene Therapy: The New Frontier for Inherited Retinal Disease

In the past 15 years, research in the field of retinal gene therapy has exploded. While no treatments have yet been approved for any inherited retinal dystrophies, clinical trials involving retinal gene therapy are creating hope for future therapies for afflicted patients. Consequently, retina specialists must now be able to appropriately diagnose counsel patients with retinal dystrophies who may be candidates for clinical trials.

This article will focus on updates in retinal gene therapy with an introduction to viral-based gene therapy, followed by a discussion of current retinal gene therapy clinical trials. The goal is to give the retina specialist a framework for evaluating and counseling these patients as they come through our clinics.

Inherited Retinal Disease: A Brief Review Inherited retinal diseases can be categorized by anatomic location in the eyethe macula, fovea, choroid or vitreous. Some diseases are more diffuse and affect all photoreceptors in the retina with varying degrees of insult to either rods or cones.

stationary or progressive. Stationary diseases are typically early onset, such as congenital stationary night blindness, whereas progressive diseases tend to be of later onset, such as retinitis pigmentosa (RP). Other inherited retinal diseases are part of larger syndromes or associated with systemic disease (Table 1).

Multiple clinical trials are ongoing for many of the diseases listed in Table 1. RP, the most common retinal dystrophy, has a prevalence of roughly 1:4,000.1 RP associated with the MERTK gene (for MER proto-oncogene tyrosine kinase) is an autosomal recessive form of the disease that is the subject of a retinal gene therapy clinical trial.2

Stargardt disease is another common retinal dystrophy (prevalence: roughly 1:8,000)3 that is the focus of multiple clinical trials, including a subretinal lentivirus gene therapy trial,4 a stem cell therapy trial5 and an oral drug trial.6 Less prevalent diseases, including Leber congenital amaurosis (LCA), achromatosopia, X-linked retinoschisis (XLRS), Usher syndrome and choroideremia, are all subjects of current gene therapy clinical trials. Given these clinical trials, the need for accurate diagnosis and counseling has substantially increased.

A typical examination of a retinal dystrophy patient starts with a detailed history, with a particular focus on family history, followed by a comprehensive ophthalmologic exam. Imagingparticularly optical coherence tomography, fundus photography and autofluorescenceelectrophysiologic testing and visual field testing can also play an important role in the evaluation.

A common misconception about inherited retinal disease is that the lack of a family history argues against a genetic origin of disease. The majority of inherited retinal diseases are passed on in an autosomal recessive pattern, and often the proband (or affected individual) is the only reported person in a large family pedigree. Children of carriers of a recessive disease have only a one-fourth chance of having the two mutated alleles.

Similarly, the likelihood for a patient with autosomal recessive disease to pass the disease to offspring is remarkably low if the other parent is unaffected, and the prevalence of the carrier state of most retinal dystrophy mutations is quite low in the general population. Obviously, consanguinity can markedly increase the likelihood of seeing recessive disease manifesta phenomenon known as pseudo-dominance. Eliciting this history in the clinical examination can help us better predict the inheritance pattern.

Once we establish a clinical diagnosis and an inheritance pattern, we may offer genetic testing for confirmation of disease.

Genetic Testing for Retinal Dystrophies The key to developing possible gene-based therapies is efficient and accurate genotyping. Gene therapy is effective only when the genetic defect is identified in a given inherited retinal dystrophy. In the past 35 years, more than 200 retinal dystrophy genes have been identified and another 50 have been mappedthat is, the chromosomal location is known but the gene has not been identified (Figure 1).

Research-based or commercially available testing has its pluses and minuses. Typically, research-based testing can be at least partially funded by grants, resulting in lower patient cost. However, not all patients are candidates for grant-funded genetic testing options and results typically take much longer to receive.

Commercial l

Gene Therapy 101 Gene therapy involves use of a vector to carry the gene of interest into the host cell. Bare DNA, nanoparticles or viruses are examples of vectors, with viruses the most commonly used in clinical gene therapy (Figure 2). Existing techniques for viral vector delivery involve intravitreal and subretinal administration (Figure 3). Future techniques may include suprachoroidal and sub-internal limiting membrane techniques.

Once a viral vector is inside the nucleus, the host cell machinery can mediate the gene expression and translation into a protein product.

Adeno-associated virus (AAV) is particularly well suited for gene therapy because it is nonpathogenic, nonimmunogenic and episomal. That is, it does not integrate into the host DNA, but rather remains separate inside the nucleus where it is effectively expressed and translated into protein.

One limitation of AAV is its packaging size; this vector can only hold a 4.7-kb transgene. Scientists have taken advantage of the ability of AAV to encapsulate and deliver DNA into human cells by manipulating the virus genome to remove genes that cause disease and insert therapeutic ones. To create an AAV vector carrying a transgene of interest, the transgene is co-transfected with the rep (or replication) and cap (or capsid) viral DNA into a packaging cell, along with helper adenovirus required for replication.

Once the helper adenovirus is eliminated, the end product is the transgene of interest carried inside a viral capsid. AAV capsids can be modified (by introducing point mutations in the viral capsid genome) to make them more efficient at transduction.

The SAR422459 trial4 (previously known as StarGen) and UshStat trials8 are using lentivirus as the vector. UshStat is a gene therapy developed by Sanofi for Usher Syndrome type 1B (USHB1).9

Lentivirus is a subclass of retrovirus in which viral genome in the form of RNA is reverse-transcribed when the virus enters the cell to produce DNA. Lentivirus is believed to integrate into the genome and can infect both dividing and non-dividing cells. Lentivirus has a much larger carrying capacity than AAV (packaging capacity of 8 to 10 kb), making it the ideal vector for treating retinal genetic disorders with larger affected genes (such as the ABCA4 gene implicated in Stargardt disease).

Replacement gene therapy is the most common clinically relevant gene therapy. It involves replacing a protein that a cell no longer expresses due to a genetic mutation in an autosomal recessive condition. This article will focus on replacement gene therapy.

Other Forms of Gene Therapy Multiple other forms of gene therapy exist. For example, a growth factor can be added in conditions where we do not know the genetic mutation or the conditions are genetically multifactorial. The Oxford Biomedica-sponsored RetinoStat trial for age-related macular degeneration involves expressing endostatin and angiostatin to provide sustained release of an anti-VEGF protein.7

Optogenetics (Box) involves genetically altering ganglion cells to become photosensitive. This would be useful in retinal degenerations in which the photoreceptors have already suffered extensive damage. For dominant conditions, we cannot replace a missing gene, so the option of suppression gene therapy arises, which involves small or short interfering RNA (siRNA).

Gene-editing techniques, such as CRISPR (clustered regularly interspaced short palindromic repeats), aim to genetically alter or modify DNA. This has been done in vitro and in mouse models, and has been used as a technique for controlling dominant/negative effect.

Surgical Considerations As we gain experience from human retinal gene therapy clinical trials, we are learning that the mode of gene therapy delivery is an important determinant of both safety and potential efficacy. The majority of retinal gene therapy trials use subretinal delivery of a viral vector to efficiently transduce photoreceptors. Preclinical animal models have reported success with subretinal delivery for transduction efficiency and rescue of the condition, so logic dictates that subretinal induction would follow in human trials.

We do not yet have a viral vector that can efficiently transduce photoreceptors via intravitreal delivery in any of the inherited retinal diseases currently in human gene therapy trials. The XLRS study utilizes an AAV vector and an intravitreal mode of delivery, but given the ubiquitous intraretinal expression of RS1 in this disease, the photoreceptors do not need to be transduced.10

The LCA2 studies offered some insight into the importance of localization of the subretinal bleb. In most of the LCA2 Phase I/II trials, subretinal blebs were placed in variable locations; some involved the fovea, others were extramacular. However, some investigators have raised concerns over the mechanical trauma that foveal detachment may induce to photoreceptors.11 Patients in gene therapy clinical trials are often young, phakic and do not have a posterior vitreous detachment, all of which are certainly considerations in surgical planning.

Instrument selection for creating the subretinal bleb is also important. Options include extendible or nonextendible cannulas, probes of 38 to 41 gauge, and manual vs. automated vector delivery. The surgeon can use the viscous fluid injector system for a foot-pedal automated injection or have a second surgical assistant manually inject the vector via a syringe and tubing system.

Another option is to create a pre-bleb with basic salt solution prior to injection of the vector to minimize the risk of losing the vector into the vitreous. Lifting the retina can take several attempts once the retinotomy is made with the cannula. Intraoperative OCT can help confirm the subretinal location of the vector.

Retinal tissue with degeneration and thinning is more prone to macular hole formation and iatrogenic retinal tears than healthy, thick retinal tissue. Typically surgeons try to not use air or gas to avoid bleb displacement. Postoperative supine positioning can maximize settlement of the bleb over the posterior pole. The timing for blebs to settle after surgery varies depending on the health of the retinal pigment epithelium and other factors.

Clinical Gene Therapy Trials Active clinical gene replacement trials are targeting Stargardt disease, Usher syndrome, RP, XLRS, choroideremia, achromatopsia and Leber congenital amaurosis 2 (LCA2) (Table 2). These trials use either AAV or lentivirus as viral vectors.

Stargardt Degeneration Trials Stargardt disease is one of the most common inherited retinal dystrophies, with a prevalence of approximately 1:8,000.3 Typical autosomal recessive Stargardt disease is associated with mutations in ABCA4 gene expressing the photoreceptor-specific ABCA4 protein, a member of the superfamily of ATP-binding cassette (ABC) transporters. Clinically, patients typically develop central visual loss as a result of progressive accumulation of lipofuscin in the RPE with the development of yellowish pisciform flecks and eventual macular atrophy.

Depending on the severity of the mutations in the ABCA4 gene, there may be a wide spectrum of phenotypes, ranging from relatively mild and late-onset localized macular disease to earlier-onset diffuse cone-rod disease. A 48-week, Phase I/IIA dose-escalation trial is investigating SAR422459, a lentiviral vector gene therapy carrying the ABCA4 gene formerly known as StarGen, for the treatment of Stargardt disease.12 Eligible patients must have two pathogenic ABCA4 gene variants confirmed by segregation analysis of parental samples.

This study is investigating vitrectomy with subretinal injection of SAR422459. The primary objective is to assess the safety and tolerability of SAR422459, with the secondary objective to evaluate biological activity. After 48 weeks, patients are encouraged to continue follow-up in a long-term safety study. At this writing, 23 patients have been enrolled, and no significant changes in best-corrected visual acuity have been reported in either the treated or untreated fellow eyes. The plan is to continue enrollment in the cohort of youngest patients with early-onset Stargardt disease and evidence of rapid progression of disease (ages 6 to 26 years; all other cohorts involve patients 18 years or older).12

Usher Syndrome Usher syndrome refers to a clinically and genetically heterogeneous group of autosomal recessive disorders which account for the most frequent cause of combined deafness and blindness in humans, with an estimated prevalence of 36:100,000.13

Usher syndrome has three clinical subtypes: USH1; USH2; and USH3. The severity and progression of hearing loss and the presence or absence of vestibular dysfunction distinguish these subtypes. USH1 is the most severe form in terms of the onset/extent of hearing loss and RP. The genetic mutation MYO7A (Usher 1B) accounts for approximately 30 to 50 percent of all USH1 cases.9

MYO7A (Myosin 7A) encodes an actin-based protein that performs critical motility functions in both the inner ear and retina. Patients with USH1B are born with profound neurosensory deafness, have vestibular dysfunction (that is, they often have a history of delay in walking), and develop early retinal degeneration in childhood.

A trial is investigating SAR421869 (UshStat), a lentiviral gene therapy administered via subretinal injection for the treatment of RP in patients with Usher syndrome type 1B (MYO7A gene defect). All patients must have two confirmed mutations in MYO7A.14 As of this writing, nine adult patients have been treated.15 A majority of these patients have shown an initial postoperative drop in BCVA and visual fields that improved to baseline within two weeks in early unpublished results. The vision was stable (in either the treated or untreated fellow eyes) after 48 weeks in a majority of patients. A separate cohort will provide the opportunity to extend the study to include pediatric patients ages 6 years and up.

X-linked Retinoschisis XLRS is an X-linked disorder that affects approximately 1:5,000 to 1:20,000 individuals.16 The disease begins early in childhood, and affected boys typically have BCVA of 20/60 to 20/120 at initial diagnosis. Severe complications such as vitreous hemorrhage or retinal detachment occur in up to 40 percent of patients, especially in older individuals.16

The causative gene was identified in 1997 and named retinoschisin 1 (RS1).15 The gene codes for the retinoschisin protein, which normally provides lateral adhesion that holds retinal cells together. RS1 gene mutations alter the protein to disrupt cell structure. Without normal retinoschisin, the layers of the retina split. Affected individuals typically have early central vision loss and can develop peripheral schisis, exudate or retinal detachment. This damage often forms a spoke-wheel pattern in the macula as seen on clinical examination and OCT.

Research has shown that intravitreal AAV delivery can rescue the condition in mice, likely due to the diffuse expression of RS1 throughout the retina as well as the relatively increased retinal permeability that abnormal retinal morphology causes.18 This is the first replacement gene therapy trial investigating the safety and efficacy of intravitreal gene delivery for an inherited retinal dystrophy.

Ongoing are two Phase I/II studies of an intravitreal-administered AAV-RS1 vector. The National Eye Institute is evaluating three different increasing dose levels of an AAV-RS1 vector in up to 24 adult patients with VA of 20/63 or worse in one eye.19 In the second study, the biotechnology company AGTC is evaluating an AAV-RS1 vector in up to 27 patients.10 The latter study involves three initial groups of adult patients receiving increasing dose levels of the vector and will also evaluate the maximum tolerated dose level in patients 6 years and older.

Choroideremia Choroideremia is an X-linked recessive disorder of a genetic defect in RAB escort protein 1 (REP1) that causes degeneration of RPE and photoreceptors. It can lead to severe and diffuse chorioretinal degeneration. Patients experience gradual vision loss starting from the periphery and advancing toward the fovea. Multiple Phase I and II trials of the AAV.REP1 vector are ongoing at several sites.

In a Phase I/II study, two patients with advanced choroideremia who had low baseline BCVA gained 21 and 11 letters in vision, respectively, despite undergoing retinal detachment.2 Four other patients with near normal BCVA at baseline recovered to within 1 to 3 letters. Maximum sensitivity measured with dark-adapted microperimetry increased in the treated eyes.

In all patients, the increase in retinal sensitivity over six months in the treated eyes correlated with the vector dose administered per area of surviving retina.20 The early improvement observed in two of the six patients was sustained at 3.5 years after treatment despite progressive degeneration in the control eyes.21

Other trials of subretinal placement of the AAV.REP1 vector are ongoing, including a Phase I/II trial Spark Therapeutics is sponsoring.22

Achromatopsia Achromatopsia is an autosomal recessive disease that affects approximately 1:30,000 individuals and is associated with the complete loss of cone function.23 Achromatopsia is of congenital-onset and relatively stationary, with clinical findings of poor central visual acuity (usually 20/200), nystagmus, severe photophobia and complete loss of color discrimination. On electrophysiology testing, patients have nonrecordable cone-mediated responses.

The two genes most commonly associated with achromatopsia are CNGB3 and CNGA3. A Phase I/II dose-escalation study sponsored by AGTC evaluating an AAV-CNGB3 subretinal vector in patients with CNGB3 achromatopsia is ongoing at four sites in the United States.24

MERTK-RP The MERTK-associated form of autosomal recessive RP is very rare, with isolated patient populations identified in the Middle East and most recently the Faroe islands.2 A Phase I clinical trial utilizing an AAV2 vector with an RPE-specific promoter driving MERTK was recently completed in Saudi Arabia.2 Six patients were treated with subretinal injection of an AAV vector expressing MERTK, without any serious adverse events. Three of these patients displayed measurably improved visual acuity in the treated eye following surgery, although two of them had lost that improvement by two years.

LCA2 (RPE65-associated LCA) Because of its early onset and the availability of multiple animal models, innovators have focused a tremendous amount of attention on developing a gene-based therapy for RPE65-associated LCA, or LCA2 (prevalence 1:100,000).25 Multiple Phase I/II trials for RPE65-associated LCA have been either completed or are ongoing. These trials have suggested that improvement in retinal function, as

Despite these promising results of early visual gain, reports of visual acuity loss after treatment30 and continued photoreceptor degeneration at three years have emerged.31 Although these findings of progressive degeneration are somewhat discouraging, they do provide context for an educated and realistic interpretation of findings from these exciting Phase I/II trials as we move into treatment trials for other inherited retinal disorders.

The recently completed Phase III trial of SPK-RPE65 for treatment of RPE65-associated LCA reported that treated patients displayed improved sensitivity to dim light compared to controls (P<0.001) with no significant difference in visual acuity between the two groups.27 The 31 subjects were randomized 2:1 to an early treatment arm or a one-year treatment- delayed arm.27 Both eyes received a subretinal injection of 300 L of AAV, with the second eye treated within 18 days of the first.

The primary endpoint for this trial was mobility testing in an obstacle course with one eye patched. Treated patients scored better than controls (P<0.001), meaning that these treated patients could navigate the maze in lower-light conditions. The secondary outcome was full-field light sensitivity, which was done with both eyes open.

The trial reported no serious adverse events. All ocular events were mild. They included transient elevated intraocular pressure in four subjects, cataract formation in three, retinal tears that resolved after laser in two subjects and transient mild eye inflammation in two subjects. Spark Therapeutics has filed a Food and Drug Administration application for approval of this therapy. That could pave the way for future retinal gene therapies and certainly raise awareness of the need for accurate clinical diagnosis of retinal dystrophies and genetic confirmation of disease.27

Optimizing Vectors, Delivery Groups are also continuing to work on optimizing vectors for potency to possibly increase the therapeutic effect of gene transfer.32 Some investigators believe that earlier treatment in these progressive retinal dystrophies may offer the best chance of sustained visual recovery. Phase I/II trials have shown no direct correlation between patient age and treatment response, although they did report less dramatic improvements in retinal sensitivity in younger patients who had the greatest preservation of retinal structure.30

The mechanism for surgically delivering gene therapy to the retina is under much discussion because of the potential trauma subretinal injections may cause, particularly those involving the macula. Some of the phase I/II LCA trials suggested that patients lost visual acuity and retinal thickness after subfoveal injections, potentially due to mechanical trauma to the fovea from inducing a retinal detachment.11

Keep in mind that these trials involving subretinal injections are targeting only cells in the region of the surgically induced subretinal bleb, which make up a small percentage of the entire retina (gene therapy clinical trial bleb sizes range from 150 m to 450 m).

Zones of retina treated, as well as viral vector dosing, play important roles in the long-term restoration of function. We may yet learn that concomitant neuro-protectant treatments are also going to be useful, if not mandatory, in treating inherited retinal degenerative disease.

Future Trials AGTC expects to begin enrollment soon of a Phase I/II dose-escalation study for treatment of CNGA3-achromatopsia with AAV (using the same AAV vector and promoter as used in the CNGB3 study).33 AGTC is also developing an AAV-RPGR vector for X-linked RP for which it plans to submit an investigational new drug application to the FDA in 2017.34

Although most phase I/II trials for LCA2 show initial improvement in retinal sensitivity in patients after gene therapy, these improvements were modest even in participants with relatively mild retinal degeneration and failed to protect against ongoing degeneration,30 suggesting that we still have much room for improvement in the field.

Research into new optimized vectors for therapeutic efficacy and longevity needs to continue. From a clinical standpoint, we still do not fully understand which patients may benefit most from therapy and how therapeutic intervention will alter the natural history of retinal degeneration and progression of vision loss. From a surgical standpoint, more attention is being placed on optimal delivery to minimize mechanical trauma and perioperative inflammation.

Retinal gene therapy has advanced eons in the past 10 years. We will likely see FDA approval in the near future for the first viral-based retinal gene therapy for LCA2. With innovations like optogenetics we can imagine a future where multiple different diseases can be treated with a larger window of opportunity for therapeutic effect. While exciting to the clinical community, these advances will be even more attractive to our patients who, until very recently, have been told at yearly follow-ups, There is nothing that can be done. We are finally at a point where we can offer realistic hope. RS

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Available at: NLM Identifier: NCT02065011. 9. Hashimoto T, Gibbs D, Lillo C, et al. Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B. Gene Ther. 2007;14: 584-594. 10. Applied Genetics Technology Corp. Safety and efficacy of rAAV-hRS1 in patients with X-linked retinoschisis (XLRS). In: Bethesda, MD: National Library of Medicine. Accessed February 7, 2017. Available at: 11. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012;130:9-24. 12. Sanofi. Phase I/IIa study of SAR422459 in patients with Stargardts macular degeneration. In: Bethesda, MD: National Library of Medicine. Available at: NLM Identifier: NCT 01367444. 13. Rosenberg T, Haim M, Hauch AM, Parving A. The prevalence of Usher syndrome and other retinal dystrophy-hearing impairment associations. Clin Genet. 1997;51: 314-321. 14. Sanofi. Study of UshStat in patients with retinitis pigmentosa associated with Usher syndrome type 1B. In: Bethesda, MD: National Library of Medicine. Available at: NLM Identifier: NCT01505062. 15. Email communication from R. Buggage, MD (February 2017). 16. Sieving PA, MacDonald IM, Chan S. X-linked Retinoschisis In: Pagon RA, Adam MD, Ardinger, HH, et al., eds. GeneReviews [Internet]. Seattle, WA:University of Washington, Seattlel 1993-2017: Accessed February 7, 2017. 17. Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997;17:164-170. 18. Min SH, Molday LL, Seeliger MW, et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of X-linked juvenile retinoschisis. Mol Ther. 2005;12:644-651. 19. National Eye Institute.; Turriff AE, Sieving PA. Study of RS1 ocular gene transfer for X-linked retinoschisis. In: Bethesda, MD: National Library of Medicine. Accessed February 7, 2017. Available at: 20. MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet, 2014. 383:1129-1137. 21. Edwards TL, Jolly JK, Groppe M, et al. Visual Acuity after retinal gene therapy for choroideremia. N Engl J Med, 2016. 374:1996-1998. 22. Spark Therapeutics. Safety and dose-escalation study of AAV2-hCHM in subjects with CHM (choroideremia gene mutations. In: Bethesda, MD: National Library of Medicine. Accessed February 7, 2017 Available at: 23. Sharpe LT, Stockman A, Jagle H, Nathans J. Opsin genes, cone photopigments, color vision, and color blindness. In: Gegenfurtner K, Sharpe LT, eds. Color Vision: from Genes to Perception. Cambridge, UK: Cambridge University Press; 1999:3-52. 24. Applied Genetic Technologies Corp. Safety and efficacy trial of AAV gene therapy in patients with CNGB3 achromatopsia. In: Bethesda, MD: National Library of Medicine. Accessed February 7, 2017. Available at: 25. Allikmets R. Leber congenital amaurosis: a genetic paradigm. Ophthalmic Genet. 2004;25:67-79. 26. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Lebers congenital amaurosis. N Engl J Med. 2008;358:2231-2239. 27. Maguire AM, Simonelli F, Pierce EA. Safety and efficacy of gene transfer for Lebers congenital amaurosis. N Engl J Med. 2008;358:2240-2248. 28. Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA. 2008;105:15112-15117. 29. Cideciyan AV, Hauswirth WW, Aleman TS, et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther. 2009;20:999-1004. 30. Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Lebers congenital amaurosis. N Engl J Med. 2015;372:1887-1897. 31. Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015;372:1920-1926. 32. Georgiadis A, Duran Y, Ribeiro J, et al. Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65. Gene Ther. 2016;23:857-862. 33. Applied Genetic Technologies Corp. Safety and efficacy trial of AAV gene therapy in patients with CNGA3 achromatopsia. In: Bethesda, MD: National Library of Medicine. Accessed February 7, 2017. Available at: 34. AGTC files investigational new drug application for the treatment of achromatopsia caused by mutations in the CNGA3 gene. [press release] Gainesville, FL, and Cambridge, MA. Applied Genetic Technologies Corp. October 19, 2016. 35. RetroSense Therapeutics. RST-001 Phase I/II trial for retinitis pigmentosa. In: Bethesda, MD: National Library of Medicine. Accessed February 7, 2017. Available at:

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Gene Therapy: The New Frontier for Inherited Retinal Disease

Nutrition : The Addiction Recovery Guide

In dealing with the chemical imbalances that are both a cause of substance abuse and a result of long-term substance addiction, nutritional therapy can be helpful in several ways.

Food and Addiction

Radiant Recovery ( This site was developed by Kathleen DesMaisons, PhD., the author of Potatoes not Prozac which charts the relationship between sugar addiction and alcoholism. It includes resources related to substance addiction plus an online program to help people deal with sugar addiction. There is also an online forum and a series of Internet-based two-week classes for $24.95 each which deal with various aspects of addiction including brain chemistry. Out-patient treatment based on this approach is also available in Albuquerque (call 505 345-3737 for further information).

Intravenous Amino Acids

Agora Regeneration Clinics ( Based in Vancouver, BC, this outpatient program focuses on biochemical detoxification of the body and brain. It includes Amino Acid IV Therapy, a Naturopathic physical work-up, infrared sauna detoxification, auricular acupuncture, massage therapy and the Agora For Life Program which deals with the emotional and mental aspects of addiction. The 10 day intensive program costs $9,800 (plus GST) and the 15 day intensive costs $13,500 (plus GST). Both program fees include the Agora for Life Aftercare program.

Nutritional Supplements, Vitamins and Herbs

Nutritional supplements such as herbs, amino acids (see chart below), vitamins and other nutrients restore the proper biochemical balance in the brain.

Supplements, vitamins and herbs can be purchased online through various websites such as,,,, and Vitamin Shoppe.

Books on Nutrition

End Your Addiction Now: The Proven Nutritional Supplement Program That Can Set You Free by Charles Gant and Greg Lewis, published by Square One (2009) can be purchased at Nutritional supplements such as herbs, amino acids (see chart below), vitamins and other nutrients restore the proper biochemical balance in the brain. These supplements are specified, according to your addiction, in an excellent book written by Charles Gant, MD, PhD, who has helped over 7,500 patients with his innovative nutritional program designed to help people addicted to drugs, alcohol, nicotine, or pain medication.

In addition, eliminating certain substances such as sugars and simple starches and increasing protein intake can help to rebalance brain chemistry. Good nutrition can also help heal damage to the body caused by the depletion of nutrients common in substance abuse.

Natural Highs by Hyla Cass M.D. and Patrick Holford published by Avery Books/Penguin Putnam in 2002 can be purchased at This book usefully reviews and gives specific doses of herbs, amino acids, nutritional supplements and foods that help a person have a sharp mind and feel happy, calm, energetic and connected to people. The main tips from this book including specific doses of herbs and amino acids can be found at

Another helpful book which has benefited many people with its nutritional advice is Seven Weeks To Sobriety: The Proven Program to Fight Alcoholism Through Nutrition by Joan Mathew Larson Ph.D. This book can also be purchased at

To Find a Nutritionist:

Academy of Nutrition and Dietetics ( Some people may decide to work directly with a nutritionist. The Academy of Nutrition and Dietetics web site can help you locate a nutritionist. This is the nation's largest organization of food and nutrition professionals. Click on the red Find an Expert button at the top of the page to locate dietitians in the United States by zip code. Descriptions include areas of practice or specialty for each dietitian.


Another important area of the use of nutrition in recovery and relapse prevention is the addition of appropriate amino acids that serve as the building blocks for powerful chemicals in the brain called neurotransmitters. These neurotransmitters, including epinephrine and norepinephrine, GABA, serotonin and dopamine, are closely tied to addiction behavior. With the use of various amino acids, brain chemistry can be changed to help normalize and restore deficiencies in the neurotransmitters that spur cravings that can lead to addiction andrelapse.

This chart was originally published in the following article. Blum K, Ross J, Reuben C, Gastelu D, Miller DK. "Nutritional Gene Therapy: Natural Healing in Recovery. Counselor Magazine, January/February, 2001

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Nutrition : The Addiction Recovery Guide

F.D.A. Speeds Review of Gene Therapies, Vowing to Target …

So far, the drug agency has approved only two products that qualify as gene therapy Kymriah, from Novartis, and Yescarta, made by Kite Pharma. Both treatments involve genetically altering a patients own immune cells to fight leukemia or lymphoma. An advisory panel to the F.D.A. recommended approval for a third product, made by Spark Therapeutics, to correct a gene defect that causes a blinding hereditary eye disease. All three agency actions occurred this year.

Such treatments are extremely expensive, costing hundreds of thousands of dollars.

The prospect of faster approvals disturbs Michael Carome, director of Public Citizens health research group, an advocacy organization. Dr. Carome believes that the industry, still quite young, needs careful F.D.A. oversight.

I think there is excessive hype, Dr. Carome said. We are talking about rushing to market very complex biologics products where we are still in the infancy of this field.

The agencys announcements included two final guidelines and two drafts that will be open for public comment. They are designed to help developers sort out whether they need to submit a licensing application to the F.D.A. to get approval for their treatments or fall into a lower risk category, which does not need premarket approval.

One of the proposals would be a boon to small clinics and independent researchers. It would permit them to apply as a group and to pool data. If approved, each would end up with a license for biologics, a category that refers to treatments like cell, tissue and gene therapies that come from natural sources rather than being chemically synthesized.

The guidelines also detail steps to rein in the hundreds of stem-cell clinics that treat ailments by liposuctioning belly fat from patients and processing it to extract so-called stem cells, which are then injected back into the patients. These largely unregulated procedures have been offered for arthritic knees, back pain, heart disease and other problems.

Several patients have been blinded after fat-derived cells were injected into their eyes.

Practitioners who perform these procedures have argued that they do not come under the agencys jurisdiction. But the new guidance suggested that at least some of the fat-derived injections will be more tightly controlled by the F.D.A. The document stated that if the fat tissue is processed specifically to isolate stem cells as the stem-cell clinics do then the procedures must meet F.D.A. safety requirements.

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F.D.A. Speeds Review of Gene Therapies, Vowing to Target ...

Cell and Gene Therapy Center – IQVIA

Developing advanced therapies involves making critical Chemistry, Manufacturing and Controls (CMC) decisions and managing complex clinical studies while navigating through an evolving regulatory and reimbursement environment.

The Cell and Gene Therapy team from IQVIA can provide the data, expertise, and services that help you transcend the challenges faced in the development and commercialization of cell and gene therapies.

Strategic and operational services customized to your therapy:

Our dedicated team of experts combine cell and gene therapy expertise with the capabilities of the IQVIA COREto address your needs throughout the development pathway.

We have a proven track record supporting a range of clients, from academics to emerging biotech and established pharmaceutical companies, in:

Comprehensive network of partners to respond to your needs:

The Cell and Gene Therapy group works in close collaboration with our alliance partners to address the unique challenges in cell and gene therapy manufacturing and nonclinical research.

Through our partnership with the California Institute for Regenerative Medicine (CIRM), we have access to the Alpha Stem Cell Clinics network that provides experienced sites for your stem-cell based therapies for more reliable and rapid study startup.

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Cell and Gene Therapy Center - IQVIA

We are currently witnessing a real breakthrough in immunological and genetic cancer therapies with innovative methods of treatment, which are virtually free of any adverse side effects as compared to chemotherapy.

The auto-vaccine or autologous cancer vaccine is derived from tissue fragments of the patient's own cancer and in the event of positive reaction the immune system becomes stimulated to recognize and destroy cancer cells, or it can significantly decrease the progression of the disease Immunotherapies, which can be used concurrently with the vaccine, are designed to activate lymphocytes in order to recognize cancer cells and to maintain the bodys defence mechanism active for a long time The new method of production of antibodies derived from cancer tissue has been covered by patents globally and it often brings impressive results. The combination gene therapy enables replacement of single sequences of DNA and it can effectively contribute to the cell transformation, its consequent repair and final regeneration. As each of us is an exceptional and orignal individual several main and accompanying therapy concepts have been proposed to treat cancer effectively and quite many of them bring astounding results. Our key objective is to support such efforts based on the continuous progress of research and with regard to promising perspectives in the future.


Hacking Your Genes Has Never Been Easier – Outside Magazine

Josiah Zayner and I are drinking fluorescent green beer at the ODIN, his Oakland lab. The tables are scattered with pipettes and disposable blue gloves, cases of Red Bull and Slim Jims are near at hand, and Drake is pulsing on the sound system. Its not St. Patricks Day, and the beer isnt really all that green. Its the ghostly luminescence of jellyfish pulsing through the depths. Thats because its chock full of glowing jellyfish protein.

But no jellyfish were harmed in the making of this beer. Zayner is the worlds most notorious biohackera new breed of garage tinkerer experimenting with DNA and biological systems outside the confines of traditional research. In this case, he genetically engineered a common brewers yeast by adding a jellyfishs green fluorescent protein (GFP) gene that he ordered online. As long as you know the DNA sequence of the gene you wantthe As, Cs, Gs, and Ts of the genetic codeyou no longer need the actual critter the gene came from. You just run off the code on a special DNA printer containing cartridges filled with liquid As, Cs, Gs, and Ts. Then you insert the new DNA into whichever organism you want to modify. The process is shockingly easy.

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I raise my glass and pause. Zayners yeast suffuses the beer with a gauzy haze. I have no idea which species of jellyfish the GFP gene came from, but my hunch is that it has never been a regular part of the human diet. Zayner assures me its safe. Genetic engineers love GFP because its such an easy visual. They include it with whichever other gene theyre trying to insert, and if their organism glows, they know the experiment worked without having to send off a sample for DNA sequencing. Scientists have engineered glowing cats and mice using GFP, he points out, and the creatures lived just fine.

I eye Zayner. He has drunk a fair amount of GFP beer himself, and while I wouldnt say he looks normalhe sports dozens of piercings, plugs in both earlobes, and a spike of bleached hair that is sometimes blue and sometimes whitehe seems healthy enough.

Dude, he assures me, we did all the normal FDA tests. Its nontoxic, nonallergenic. As further proof, he shows me his left forearm. Right next to the tattoo that says CREATE SOMETHING BEAUTIFUL is a row of four tiny wounds. I modified myself with it. Its fine.

Agar plates and vials of microbes at the ODIN lab. (Justin Kaneps)

Zayner claims he was the first to genetically modify himself with another speciess DNA. For what he would call a science experiment and I would call conceptual art, he removed dead skin cells from his forearm (just rub the same spot with a toothbrush 200 times) and used a tattoo needle to punch jellyfish DNA into his skin. The DNA was attached to a common virus that specializes in infiltrating human cells and parking itself there. Those skin cells then began manufacturing the GFP along with all their regular proteinsthough, to Zayners disappointment, not enough to see the glow with the naked eye. He also performed a DIY fecal transplant on himself, which was chronicled in the recent documentary Gut Hack, curing himself of years of irritable bowel syndrome.

Im not sure what I think about any of this, starting with my beer. I tend to favor pilsner over jellybrew, but Im trying to maintain my chill biohacker persona, so I chug. Weve spiked it with enough blood orange juice to cover any weirdness, and frankly it goes down pretty easy. Just like that, this crunchy Vermonter who always shunned GMOs filled his belly with them, and starts looking forward to the week ahead.

Id always thought of genetic engineering as something done in million-dollar labs by corporate powerhouses like Monsanto. Extracting the DNA from life forms and inserting it into other life forms seemed like the kind of thing that required high-tech machines and years of trial and error. And it used to. But that was before Crispr, Science magazines 2015 Breakthrough of the Year, an engineered protein that can snip out sequences of DNA wherever you want. Its like a search and replace function for genes. It works on bacterial cells, it works on mouse cells, and it works on human cells. Its been used to engineer immune cells that kill cancer, viruses that kill antibiotic-resistant bacteria, female mosquitoes that cant reproduce (to crash the population), and a yeast infused with genetic code from poppies and rats that makes opioids out of sugar in a tank. But the crazy thing about Crispr is that its so easy to use and cheap to make that it also allows any budding hacker with some basic biology and a mischievous mind to play God in their garage.

The only thing missing is someone to share this knowledge with the multitudes, and thats where Zayner comes in. He started out traditionally enough: wunderkind Ph. D. candidate at the University of Chicago and then research fellow at NASA, where he adapted organisms for life on Mars. But then, in 2015, he veered off to become the pierced Prometheus of genetic engineering, bringing it down to us mortals from the labs of academia. In this field, there are a bunch of people with a lot of knowledge and a bunch of people with a lot of crazy, he says with a smile, but there are very few with a lot of knowledge and a lot of crazy.

Not for the first time, I smile back at Zayner and try to gauge the crazy. For now Im coming down on the side of like a fox. Hes made a huge success of the ODINshort for Open Discovery Institute and inspired by the Norse godthe combination lab and mail-order business he founded in 2013 to make DIY bio accessible to everyone. The ODIN sells pre-engineered GFP yeast ($80) online, along with DIY Crispr kits ($150), fluorescent-yeast-engineering kits ($160), something called the Amino DNA Playground ($349), and a complete Genetic Engineering Home Lab Kit ($999) stocked with pipettes, tubes, scales, antibiotics, agar, light-activated bacteria, bioluminescent bacteria, Crispr, and a PCR machine, which makes copies of DNA through polymerase chain reaction. The ODINs clients include community colleges, high school kids, and mysterious individuals.

Jars of Crispr. (Justin Kaneps)

All ODIN kits are designed to engineer bacteria or yeast, the cheapest and simplest critters to work with, and they focus on obvious visuals like GFP. They are the Easy-Bake Ovens of genetic engineering. They offer quick success to rank amateurs like me and a tantalizing taste of the endless possibilities. Where we take it from there is up to us.

Zayner and his fellow biohackers are big on genetic freedom. Everything your body makes or does is encoded by a gene. And the more we learn about the genetic basis of human processesfrom disease and life expectancy to athletic and mental performancethe closer we get to being able to reprogram our bodies. I think we could do substantial changes to ourselves right now, Zayner says. You could go a little more crazy than scientists have been willing to let on.

For years there have been rumors that people already are. Gene doping, as its called, could theoretically give anybody the ability to burn oxygen like a Tibetan mountaineer, to build muscle like LeBron James, and to never get heart disease. Its all in the genes. Its in the hard work and good habits, too, but without certain tools you can only go so far. And in either the shady present or the not so distant future, well all have access to those tools, which Zayner finds pretty exciting. This is the first time in human history that were no longer stuck with the genes we had at birth. It fucking blows your mind.

He sees no reason to let corporations and ivory-tower institutions have all the fun. Hence the Easy-Bake Ovens. Give a man a cookie and he eats for a day. Teach a man to cook and youve stolen fire from the gods.

Josiah Zayner. The name screams Marvel Comics. The backstory, too: Country childhood on an Indiana farm. Pentecostal parents. (His brothers are Micah, Zachariah, and Jedediah; the dog was named Jeremiah.) Missionary in Peru. Teenage member of the late-nineties hacker collective Legions of the Underground. Biophysics Ph.D. from the University of Chicago. Synthetic-biology fellowship at NASAs Ames Research Center. Then something goes horribly wrong.

In Zayners case, there was no lab explosion. No rampaging through the streets of Mountain View, paralyzing Google employees with jellyfish tentacles sprouting from his back. No, what went wrong is that Zayner discovered that NASA was deadly dull. Empty offices. Stultifying bureaucracy. A supervisor who actually told him to spend less time in the lab. Not the place for someone who wanted to change the universe. So he did what any budding superhero would do: he went rogue.

Crispr and pipettes. (Justin Kaneps)

As his two-year NASA fellowship neared its end in 2015, Zayner launched an Indiegogo campaign offering contributors their own DIY gene-editing kit. Hed learned just enough while getting his Ph.D. to realize that genetic engineering was way more accessible than most people knew, and he couldnt wait to liberate it from the elite labs he loathed and bring it to the people, because, as he told me, I was always that poor-as-dirt kid dreaming that he could do some great experiment. The pitch video featured shots of Zayner swigging from a flask at the lab bench (his kitchen counter) while the voiceover asked, If you had access to cutting-edge syntheticbiology tools, what would you create? The campaign raised more than $70,000.

It also freaked out critics. Zayners campaign is worrisome because it does not seem to comply with the code of conduct, Todd Kuiken, a scholar in the Genetic Engineering and Society Center at North Carolina State University, wrote in Nature in 2016. He was referring to the nonprofit founded in 2008 to foster safe practices in DIY biology. For example, he noted, The video that accompanies his campaign zooms in on petri dishes containing samples that are stored next to food in a refrigerator. Kuiken also believes there needs to be a robust public dialogue about the responsible use of Crispr.

The refrigerator comment still annoys Zayner. So are you saying that being able to do science is a class thing? Only people who can afford second fridges should do science? But he got his act together and bought another fridge, in part because he was already under scrutiny from the FDA, which had threatened to seize his equipment because of his Internet sales. Zayner has also been warned of possible prosecution by officials in Germany, where biohacking is banned. But the practice is perfectly legal throughout the United States, mostly because it has never occurred to legislators to outlaw such a thing, and the ODIN is doing well. Zayner sells thousands of gene-editing kits globally every year, and he expects to gross at least $400,000 in 2017. The world wants this.

The workday at the ODIN starts late-morning. One employee is multi-tasking, packing kits for the days orders while he propagates new batches of microbes. Zayners brother Micah is scarfing Chinese takeout on the couch. The air is redolent with the funk of E. coli bacteria and young male. Zayner solders new wiring onto used PCR machines (There are few things Im one of the worlds leading experts on, but finding functional lab equipment on eBay is one of them, he says) while guiding me through an attempt to engineer antibiotic resistance into E. coli using Crispr. Despite the punk trappings, Zayner is gentle, kind, and a very good teacher.

We rehydrate some dried E. coli in a test tube, pour it into a petri plate containing nutrients, and set it aside overnight. In the morning, we have a flourishing colony of fuzzy white bacteria. We scrape it up, divide it into two plastic tubes of liquid, and to one tube add a few drops of Crispr programmed to change a single A to a C, which will flip the electrical charge of a protein in the bacteria from positive to negative at the point where streptomycin normally attacks it, repelling the antibiotic molecules. Then we pour the two batches onto fresh agar plates laced with streptomycin and incubate everything at 99 degrees for 24 hours.

Genetically modified beer. (Justin Kaneps)

The next day, I pull our agar plates out of the incubator and examine them. Eureka! The normal bacteria is stone-cold dead. But the plate with the modified bacteria is studded with survivor colonies. Weve created GMOs in a day. They and their trillions of descendants will be immune to streptomycin.

Or they would have been if we hadnt killed the whole colony with bleach and thrown it in the trash. As crazy as our creation sounds, it turns out that it was pretty innocuous. This particular version of antibiotic resistance is so simplejust a single changed letter of DNAthat bacteria come up with it on their own all the time. We werent introducing anything the world hadnt seen before, and anyway our weak lab strain was about as dangerous as a cocker spaniel. Yet I cant help but wonder about all the biohackers out there who arent bleaching their experiments. What could the wrong person do with this knowledge?

Thats what I asked Ed You, the biological-countermeasures specialist at the FBIs Weapons of Mass Destruction directorate. You is the governments point person on bioweapons; its his job to worry about this stuff, but he had bigger things on his mind than the ODIN. The most dangerous bioterrorist out there is Mother Nature, he told me over the phone. Were getting hit with emerging and reemerging infectious diseases all the time. Bird flu, MERS, SARS, Zika, West Nile. If you think about a clear and present danger, its that. So we absolutely need the innovation that comes from the life sciences, from DIY bio, to make sure we develop the right counters.

Wait a minute, I said. You actually want them out there tinkering? Yes, he replied. Biology is proliferating quickly, but how do we address security in a way that doesnt handicap forward progress? If you shut down DIY bio, then you run a completely different national-security problem. If you stifle innovation, then youre going to be missing out on opportunities to come up with new vaccines, new biodefense, new countermeasures, new businesses. And if that happens, then youve developed a whole different kind of vulnerability.

You pointed out that the field was moving so fast that agents could never keep up with the pace of the advances. Instead, hes cultivated a neighborhood-watch mentality among the countrys scientists and biohackers. Theyre best positioned to see where the advances are coming from, he said. If someone like Josiah gets a suspicious order of some kind, he knows that hes got a local coordinator in the San Francisco field office he can contact.

Agar plates. (Justin Kaneps)

It all sounded strangely progressive for a bunch of G-men, but every expert I consulted told me that they had no concerns about Zayner. Forget the garagistas, they told me; worry about the academics. Many labs now have the technology and know-how to make some fearsome beasties. Last year, a scientist in Canada shocked the world when he managed to bring to life horsepox, a smallpox cousin that went extinct in the 1980s, by synthesizing its DNA from a sequence stored in a computer database. Are we entering a new era of bioterror?

Probably not, Zayner told me. Lets imagine youre the worst person in the world and you want to hurt people with biologicals. First you have to have the knowledge. Then you have to have the facility. Then you have to think about how its going to spread. It would be an astounding feat. Could you kill one or two people? Sure. But you can do that with a fucking kitchen knife.

That night, Zayner and I celebrate our successful biohack over pig-ear fries and sake at a Korean joint before heading over to Counter Culture Labs, a communal biohacker space where he occasionally teaches. Amid the lab benches and anarchist posters are shelves of strange plants under grow lights and a pig heart in a vat. One woman is attempting to create vegan cheese by inserting cow milk-producing genes into yeast, while another man is quietly sequencing the DNA of the mushrooms he collects in Mexico each summer. A small team are hard at work designing an organism that can produce human insulin. In keeping with the hacker ethos, they will gift it to the world open-source.

There are dozens of biohacker enclaves like this around the globe, such as Genspace in Brooklyn, New York, where hipsters can take Crispr classes and attend Biohacker Boot Camp. The U.S. has been the hub, but now Europe is coming on strong. has nearly 5,000 members in its Google Group and boasts 99 local chapters, from Madison to Mumbai. Most biohackers never get beyond simple experiments with microbes, but a few have taken it further. David Ishee, a dog breeder in Mississippi, is editing heritable diseases out of his dalmatians. Sebastian Cocioba, a plant hacker in New York, engineered a pioneering blue rose gene, using a DNA sequence from a tropical clam that produces an intensely blue protein, as well as a beefsteak tomato that produces cow protein in its flesh. Cocioba, who operates out of his 12th-floor apartment in Long Island City, is so skilled that he has been asked by MIT to spearhead a top-secret flower project, the details of which cant be shared except to say that in a few years it will capture the worlds attention.

And what about people? I ask. How long before cyclists start giving themselves the EPO gene to produce more red blood cells, or lifters start playing around with the gene for human growth factor?

Zayner laughs. Dude, either people are already doing that shit, or its going to start immediately. Id be very surprised if there isnt somebody out there doing it already. Its so hard to test for. What are you going to do, look for DNA? If a professional athlete came to me right now and said, Ill give you $100,000 to make me a piece of DNA, Id be like, Hell yeah.

Zayner believes we should all have access to DIY bio. (Justin Kaneps)

Surprisingly, this is perfectly legal, though its long been banned by sporting organizations. Athletes and life-extension buffs have been sniffing around gene-therapy clinics for years, ever since pioneering physiologist Lee Sweeney, from the University of Pennsylvania, showed that mice injected with the gene IGF-1, or insulin-like growth factor, significantly increased their muscle mass. Sweeney has also shown that mice injected with endurance genes were able to run 70 percent farther on the wheel than their unmodified peers, and that couch-potato mice ran 44 percent farther.

Just this June, a team of U.S. and Israeli scientists announced the discovery of a rare genetic mutation linked to ten years of extra longevity in men. And in 2015, Liz Parrish, the CEO of the startup BioViva, announced that she was the first person to attempt to reverse her own aging with gene therapy. I am patient zero, she wrote on Reddit. I will be 45 in January. I have aging as a disease. Parrish traveled to a clinic in Colombia (the therapy isnt approved in the U.S.) and received injections of one gene to extend the lifespan of her individual cells and another to block myostatin, the hormone that regulates muscle deterioration.

Myostatin is the holy grail of potential dopers who believe they can both arrest the natural deterioration of muscle and build more in their youth. Muscle is metabolically expensive to maintain, so myostatins job is to stop new muscle from being made once youve got enough and to atrophy muscle you arent using. You can find images online of dogs, cows, and people with a rare mutation that shuts down the myostatin gene and turns them into Incredible Hulks. Scientists in China recently used Crispr to turn off the myostatin gene in two beagles. The dogs look healthy, happyand ripped.

But Im less interested in what athletes are doing than in something Zayner said to me on my first day in the lab: This is the first time in history that were no longer stuck with the genes we had at birth. If Zayner has his way, well all be sculpting our own evolution.

Lets be clear: dont try this at home! Although hundreds of gene-therapy trials are under way, and many experts believe they will eventually transform almost every aspect of human health, few have been proven safe. When you start scrambling your DNA, very bad things can happen. You can get cancer. Your immune system can attack the unfamiliar DNA, as happened when an 18-year-old with a rare metabolic disorder died during a University of Pennsylvania gene-therapy trial in 1999.

But sick people wont wait for years of trials, Zayner says. He hears regularly from people willing to roll the dice. Hes been consulting pro bono for a man using Crispr to treat his own Huntingtons disease and another who is treating his 32-year-old wifes advanced lung carcinoma with genetically engineered DNA vaccines. A lot of people contact me with stuff like thatIm suffering. Can you help?

Zayner sticks to the free advice, helping people figure out the sequence of the DNA they need without supplying anything himself, but he knows where this is headed. The only thing holding people back is morality. I have no doubt there are places in Singapore or Thailand or the Philippines doing it. They could totally create individualized cancer treatments right now. Clinics will pop up. Youll go to shops in the back alleys of Bangkok and hand $10,000 to a synthetic biologist and hell take a blood sample and make you up a vaccine in a couple of days.

Im flashing back to Blade Runners replicant shopsI just do eyeswhen Zayner gets a funny smile and cocks his head. Want to try something kind of creepy Ive been thinking about?

For our final piece of conceptual art, Zayner and I swab the crevices of our skin and inside our mouths with Q-tips and swirl the gunk into tubes of distilled water. We spread the contents over agar plates and incubate them overnight.

The next morning, Josiahthing is nearly barren, but Rowanthing is crawling with cells. Look at those big fat yeasties! Zayner mutters with envy. All I can think is, if this works, it will give new meaning to the term homebrew.

We scrape up some Josiahthing and Rowanthing and put each in its own microcentrifuge tube with some chemicals that soften up cell walls so new DNA can get inside. We pipette ten microliters of the jellyfish DNA into each tube, shake them up, let them sit for a few hours, then pour them across new agar plates and cross our fingers. If this actually works, I might make it a kit, Zayner muses.

By then I have to catch a flight home, so I tape up my petri plate and pack it, along with yellow-tint glasses and a blue LED, which makes the fluorescence easier to see. TSA doesnt bat an eye.

The next day I get an e-mail from Zayner: Any growth on that plate?

Yep! Four or five nice, puffy little white colonies.

Put on the glasses and shine blue light on them. Do they glow?

I don the glasses and hit the plate with the blue LED. There are a dozen tiny colonies that stay dull under the light, but there are also five large conical colonies fluorescing like the Green Goblin. Totally! I write back, and send a photo.

Amazing! So cool! So jealous. Mine didnt work.

I feel as proud as Victor Frankenstein. Ive created life from my own spit. In the following weeks, Rowanthing develops an apex so green you dont even need the glasses to see it. Whatever it is, its new to this planet, and its burbling away in my basement, waiting to meet the world.

Contributing editor Rowan Jacobsen (@rowanjacobsen) is a Knight Science Journalism Fellow at MIT. Justin Kaneps(@Justkaneps) is anOutsidecontributing photographer.

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Hacking Your Genes Has Never Been Easier - Outside Magazine

Quick Hits: Withdrawn Leukemia Drug Returning, Drugmaker in $58M Settlement Over Sales Reps, and More – MedShadow (registration) (blog)

The leukemia drug Mylotarg (gemtuzumab ozogamicin), which was voluntarily withdrawn from the market in 2010 over safety concerns and questions about its efficacy, is available again. The FDA has approved the biologic for adults with newly diagnosed acute myeloid leukemia and for patients at least 2 years old who have had a relapse or didnt respond to prior treatment. Mylotarg originally received accelerated approval in 2000 for older adults who had experienced a relapse. But it was removed from the market after patient deaths and a lack of clinical benefit were observed in confirmatory trials. With the new approval, Mylotarg now has a lower recommended dose, a different schedule of how often the drug is given, and a different patient population. Pfizer, Mylotargs manufacturer, presented the FDA with additional data, analysis and research from clinical trials that lasted for 10 years in support of re-approval. The FDA said it allowed Mylotargs return after careful examination and based on the benefits outweighing the risks. Posted September 1, 2017. Via FDA.

Novo Nordisk has agreed to pay $58 million over allegations that some of its sales representatives downplayed a cancer risk associated with its diabetes drug Victoza (liraglutide) in marketing to doctors. When Victoza was approved in 2010, the FDA mandated it come with a Risk Evaluation and Mitigation Strategy (REMS) that required the drugmaker to provide information regarding Victozas potential risk of medullary thyroid carcinoma (MTC) a rare form of cancer associated with the drug to physicians. According to a complaint filed by the US Department of Justice (DOJ), some Novo Nordisk sales representatives created a misleading impression that the cancer risk associated with Victoza was incorrect or unimportant. In addition, they failed to accurately report important data regarding the drugs safety and efficacy. The DOJ also noted that a survey in 2011 found that half of primary care doctors polled said they did not know about the MTC risk. Posted September 5, 2017. Via US Department of Justice.

The FDA has approved the first-ever gene therapy, Kymriah (tisagenlecleucel), as a treatment for children and young adults for a type of leukemia. The immunotherapy is considered a breakthrough since it is made using the patients own T-cells, white blood cells that are part of the bodys immune system that fight infections and cancer. Kymriah is custom-made for each patient. A patients T-cells are sent to a manufacturing facility and then modified genetically to include a gene that has a specific protein that tells the T-cells to find and kill leukemia cells. After the modification, the T-cells are infused back into the patient. Researchers found that Kymriah led to remission of acute lymphoblastic leukemia in 83% of 63 children and young adult patients within 3 months. Despite the benefits, the treatment carries risks, including a boxed warning about a potentially fatal immune reaction known as cytokine-release syndrome. Other severe side effects seen with Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever and decreased oxygen (hypoxia). Because of these risks, the FDA is requiring that hospitals and clinics that want to dispense Kymriah need to be certified and their staff involved in the treatment trained to recognize and manage symptoms. Posted August 30, 2017. Via FDA.

Alanna McCatty is a recent graduate of Pace University with a degree in communications. At MedShadow, she reports on new findings and research on the side effects of prescription drugs.

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Quick Hits: Withdrawn Leukemia Drug Returning, Drugmaker in $58M Settlement Over Sales Reps, and More - MedShadow (registration) (blog)

FDA approves first cell-based gene therapy for use in the United States – Gears Of Biz

The U.S. Food and Drug Administration issued a historic action today making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases.

The FDA approved Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

Were entering a new frontier in medical innovation with the ability to reprogram a patients own cells to attack a deadly cancer, said FDA Commissioner Scott Gottlieb, M.D. New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, were committed to helping expedite the development and review of groundbreaking treatments that have the potential to be life-saving.

Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patients own T-cells, a type of white blood cell known as a lymphocyte. The patients T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.

Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease, said Peter Marks, M.D., Ph.D., director of the FDAs Center for Biologics Evaluation and Research (CBER). Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.

The safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent.

Treatment with Kymriah has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects of Kymriah include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah. Since the CD19 antigen is also present on normal B-cells, and Kymriah will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.

The FDA today also expanded the approval of Actemra (tocilizumab) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within two weeks following one or two doses of Actemra.

Because of the risk of CRS and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah are required to be trained to recognize and manage CRS and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.

The FDA granted Kymriah Fast Track, Priority Review, and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDAs Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.

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FDA approves first cell-based gene therapy for use in the United States - Gears Of Biz

FDA Approves New Cancer Treatment – Alive For Football

Analyst John Newman of Canaccord takes yesterday's FDA approval of Novartis' chimeric antigen receptor T-cell (CAR-T) therapy Kymriah as a meaningful victory for Kite Pharma Inc's (NASDAQ:KITE) fellow CAR-T therapy candidate Axi-cel.

"We're entering a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer", said FDA Commissioner Scott Gottlieb.

An FDA advisory committee had recommended the therapy for approval in July to treat the relapse of a blood cancer known as B-cell acute lymphoblastic leukemia, or ALL. While this was a groundbreaking approval, the therapy will cost $475,000 for 1 treatment, according to Kaiser Health News.

The CAR-T cell treatment developed by Novartis and the University of Pennsylvania is the first type of gene therapy to hit the USA market - and one in a powerful but expensive wave of custom-made "living drugs" being tested against blood cancers and some other tumors, too.

Most patients with ALL recover through other treatments such as radiation, chemotherapy and stem cells. The FDA said hospitals and clinics must become certified to distribute the treatment, meaning they are prepared to recognize and treat CRS and other potentially fatal neurological events.

Each dose of Kymriah contains a patient's own immune cells, which are sent to a lab to be genetically modified using a virus. Once re-injected into the patient's body, the T cells modified to replicate quickly, and the remission is rapid.

The therapy is being licensed and brought to market by the pharmaceutical company Novartis.

"Novartis is collaborating with (Centers for Medicaid Services) to make an outcomes-based approach available to allow for payment only when pediatric and young adult ALL patients respond to Kymriah by the end of the first month".

The price of the therapy is tagged at around $500,000. An immune overreaction called "cytokine release syndrome" can trigger high fevers, plummeting blood pressure and in severe cases organ damage, requiring special care to tamp down those symptoms without blocking the cancer attack. Because Kymriah can have life-threatening side effects, including unsafe drops in blood pressure, the FDA is requiring that hospitals and doctors be specially trained and certified to administer it, and that they stock a certain drug needed to quell severe reactions.

For now, it is only approved for use on ALL.

Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, is excited by the drug's approval, but he has some reservations. This is elegant science. "There is still much more work to do", Lichtenfeld told Healthline. The safety and effectiveness of Kymriah was tested in one small clinical trial of 63 children and young adults with relapsed or refractory B-cell precursor ALL. Even then, it is prescribed only as a last resort when other forms of treatment have failed.

Still, "a far higher percentage of patients go into remission with this therapy than anything else we've seen to date with relapsed leukemia", said Dr. Ted Laetsch of the University of Texas Southwestern Medical Center, one of the study sites.

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FDA Approves New Cancer Treatment - Alive For Football