Category Archives: Genetic Therapy

INDIANAPOLIS A dime-size nanochip developed by a world-renowned researcher who recently relocated to Indianapolis could help transform the practice of medicine. It could also turn Indianapolis into a manufacturing and research hub for radically new disease and trauma treatment techniques.

It all began in August 2018, when Chandan Sen, one of the worlds leading experts in the nascent field of regenerative medicine, moved his lab from Ohio State University to the Indiana University School of Medicine. He brought along a team of about 30 researchers and $10 million in research grants, and now serves, among a myriad of other positions, as director of the newly formed Indiana Center for Regenerative Medicine and Engineering, to which IU pledged $20 million over its first five years.

IU recruited Sen away from Ohio State in part because of its desire not just to promote academic research in his field but also to help develop practical, commercial products and uses for his breakthroughs.

A scientist prefers to be in the lab and keep on making more discoveries, said Sen, 53.

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But I thought that, unless we participate in the workforce development process and the commercialization process, I dont think that the business people would be ready to do it all by themselves. Because its such a nascent field.

Its definitely new and its potential sounds like the stuff of science fiction.

Regenerative medicine, as its name hints, seeks to develop methods for replacing or reinvigorating damaged human organs, cells and tissues.

For instance, instead of giving a diabetic a lifetimes worth of insulin injections, some of his skin cells could be altered to produce insulin, curing him. Such techniques might also be used for everything from creating lab-grown replacement organs to, someday, regenerating severed limbs.

Regenerative medicine offers a form of medicine that is neither a pill nor a device, Sen said.

It is a completely new platform, where you dont necessarily depend on any given drug, but are instead modifying bodily functions.

A big, tiny breakthrough

Sen and his teams signal contribution to the field is a technique theyve dubbed tissue nanotransfection, or TNT. Put simply, it uses a nanotechnology-based chip infused with a special biological cargo that, when applied to the skin and given a brief electrical charge, can convert run-of-the-mill skin cells into other cell types. Potentially, the technique could be used for everything from regrowing blood vessels in burn-damaged tissue to creating insulin-secreting cells that could cure diabetics.

Obviously, such applications are still down the road a ways. But the technology is far enough along that some products are already making it to marketand investors, entrepreneurs and established companies are sniffing around for opportunities. According to the Alliance for Regenerative Medicine, more than 1,000 clinical trials worldwide are using regenerative medicine technologies.

Thousands of patients are already benefiting from early commercial products, and we expect that number will grow exponentially over the next few years, said Janet Lambert, the alliances CEO.

Lambert predicts that the number of approved gene therapies will double in the next one to two years. Last year, the U.S. Food and Drug Administration predicted it would be approving 10 to 20 cell and gene therapies each year by 2025.

These new techniques could do more than just revolutionize medicine. They could also upend the medical industry as we know it. And the IU School of Medicineand Indianapoliscould lead the way.

There are really only two or three places in the country that did the kind of comprehensive work that Dr. Sens group was doing, said Anantha Shekhar, executive associate dean for research at IU School of Medicine. And they were doing it from the lab all the way to the clinic, where they were already applying those technologies in patients.

So it was very attractive to think of starting with a bang bringing a comprehensive group here and creating a new center.

Ambitious goals

Instead of merely treating chronic conditions, regenerative medicine could end them, once and for all.

For instance, consider a car with an oil leak. The traditional medical approach might be to live with the chronic condition by pouring in a fresh quart of oil every few days. The regenerative medicine approach would fix the leak. Its good for the car, good for the cars owner but not necessarily good for the guy who was selling all those quarts of oil.

Which is why these new techniques, if they catch on, could cause turmoil in the medical industry.

Because regenerative medicine has the potential to durably treat the underlying cause of disease, rather than merely ameliorating the symptoms, this technology has the potential of being extremely disruptive to the current practice of medicine, Lambert said.

This has the potential to be hugely disruptive, Sen added, because so much of medicine today relies on huge industrial infrastructures to manage, not cure, chronic diseases and disabilities.

If such disruption comes to pass, the leaders of 16 Tech, a 50-acre innovation district northwest of downtown that aspires to house dozens of medical-related startups and established firms, would love to be its epicenter.

The Center for Regenerative Medicine will be one of the tenants of 16 Techs first building, a $30 million, 120,000-square-foot research and office building scheduled to open in June.

Regenerative medicine is probably one of the next major waves of medical innovation in the world, 16 Tech CEO Bob Coy said. To have him here doing this work gives Indianapolis and Indiana an opportunity to develop an industrial cluster in regenerative medicine.

Coy believes the most momentous early step on that road was the recent establishment by Sen of masters and doctoral programs in regenerative medicine at the IU School of Medicine. Its the first degree of its type in the country, earning IU and Indianapolis the enviable status of first mover.

I think, for example, of [Pittsburghs] Carnegie Mellon University, which, back in the late 1960s, created the first college of computer science in the country, Coy said. And now you know Carnegie Mellons reputation in computer science.

What isnt in place yet is a state or city program to promote development of a regenerative medicine hub.

We need to start doing that, Coy said. That means putting a lot of the infrastructure in place to support startups that are based on this technology, as well as recruiting companies that want to collaborate with Dr. Sen.

In spite of the lack of a coherent recruitment program, Coys phone has started to ring, thanks largely to Sens presence.

There have been a few meetings Ive had with people who already have relationships with him, who, when they come to town, have reached out to meet and talk about what were doing at 16 Tech, he said.

Fueling entrepreneurship

One of the first 16 Tech startups with designs on the regenerative medicine niche is Sexton Biotechnologies.

The company was groomed by Cook Regentec, a division of Bloomington-based Cook Group charged with incubating and accelerating technologies for regenerative medicine and the related field of cell gene therapy.

Any products that show promise are either folded into the company, turned into their own divisions or, as in Sextons case, spun off as an independent entity with Cook retaining a financial stake.

Its a measure of the newness of this field that Sextons 17 employees arent working on new medicines, but rather marketing basic tools needed to conduct research. The companys offerings include a vial for storing cell and gene products in liquid nitrogen, and a cell culture growth medium.

Theres a ready market for such tailor-made gear, because, for years, researchers in the regenerative medicine field had to make do with jury-rigged equipment.

What most of those companies did was repurpose things like tools from the blood banking industry, or tools from bio pharma, said Sean Werner, Sextons president.

So thats why a lot of newer companies are starting to build tools explicitly for the industry, as opposed to everybody just having to cobble together stuff that was already out there.

Werner said investors recognize the momentous opportunity in regenerative medicine and are flocking to the field.

Its not something you have to explain, he said. Companies and VC groups are trying to get a piece of it.

What has investors and medical researchers charged up is the almost unlimited range of potential applications, from healing burns to, perhaps someday, regenerating limbs.

I think it would be a huge revolution if were able to, for example, regenerate insulin-secreting cells in children who have become juvenile diabetics or have for whatever reason lost their pancreas, Shekhar said. Those are the kinds of things that will start to change the way we see certain diseases.

Lambert predicted that, as the science advances, so will the business case.

While early programs focused primarily on rare genetic diseases and blood cancers, were already seeing the field expand into more common age-related neurological disorders, such as Parkinsons and Alzheimers, she said.

I expect this trend to continue in the coming years, greatly increasing the number of patients poised to benefit from these therapies.

Werner said regenerative medicine also is seeking advancements in manufacturing technologies that will lower the cost of product development.

It all adds up to a huge opportunity the state is well-positioned to seize, Werner believes.

Indiana is a perfect place for this kind of thing to really ramp up, he said. Theres no reason we cant lead the field.

Read this article:
IU team pursuing breathtaking advancements in regenerative medicine - The Republic

Gene therapy does more than treat genetic diseases it can cure them. A one-time dose of a non-replicative viral vector, such as commonly used recombinant adeno-associated virus (AAV), delivers a functional gene to replace or compensate for a dysfunctional version that is causing a patients disease (Figure 1). As a cutting-edge biopharmaceutical technology, there are multiple gene therapies now FDA approved; with hundreds more in clinical trials, were likely to see many more of these therapies on the market soon.1 However, to keep up with the rapid pace of clinical research, developers are working to streamline the manufacturing and quality control process to improve quality and lower the cost of bringing these important drugs to market.Developers use a multitude of analytical tests to develop gene therapies and optimize their manufacturing process. When developers get aberrant test results, they must be able to interpret where the problem lies. Did the manufacturing process produce an undesirable product, or is the analytical testing method unreliable? Analytical testing companies that have the infrastructure, personnel, and experience often partner with developers to tighten up analytical variability so that results of tests clearly indicate where there are opportunities to increase efficiency and product quality.

Figure 1. Gene delivery by recombinant viral vector.During gene therapy, viral capsids containing the therapeutic gene are taken up by the patients cells and the genetic material is delivered to the nucleus. There, the gene gets expressed as a protein necessary for the patients health. Credit: Avomeen.

Figure 2. A full AAV capsid and associated capsid impurities. Complete viral capsids have AAV are assembled from 60 capsid proteins, with a defined stoichiometry and shape and contain a therapeutic gene. AAV vector impurities include capsids that contain too many copies of the gene (overfilled), those that contain lower copy numbers or truncations of the gene (partially full), or empty capsids that contain no genetic material. Credit:Avomeen.

There are several ways to measure the empty/full capsid ratio, and as developers are establishing their chemistry, manufacturing and control (CMC) protocol, it is important that they choose an optimized method, as they must use that method for effective quality control from early process development to lot release and stability.3 Gene therapy developers may choose analytical ultracentrifugation to evaluate capsids, but while highly effective, this method is not as quantitative, robust or efficient as some newer methods. High-performance liquid chromatography (HPLC) using AAV full/empty analytical columns have been demonstrated to be highly effective at separating full, empty, and improperly filled capsids for robust quantification. Additionally, this method is higher throughput than ultracentrifugation, and requires less precious AAV sample to run.

Cellular potency is evaluated by transducing cells with the AAV product and then measuring a phenotypic or functional outcome due to the transduction. Developing these tests can be challenging because there is no one-size-fits-all test that will give developers the answers they need. Developers often draw on the experience of analytical labs to determine how to best evaluate their AAV products transduction efficiency.A gene therapy in development must also be tested to ensure that it is free of residual, process-related impurities such as polyethylenimine, iodixanol, poloxamer, and other excipients that must be removed in the final product to ensure safety. Few research and manufacturing facilities have the equipment and expertise necessary to perform this kind of testing, and it is advisable to find one that has experience testing polymers, extractables and leachables to examine if components of the manufacturing equipment or drugs packaging are not contaminating the final product.

As fast-paced as the gene therapy field is now, it stands to become a true race to the finish line to bring new gene therapies to market in the near future. Regulatory bodies are becoming more familiar with reviewing gene therapies, and the road to commercialization will move more quickly. There is no denying that gene therapies will bring incredible benefits to patients, but it will be crucial to improve manufacturing efficiency and lower costs to make gene therapies more accessible to the patients who need them.References

1. Colasante, W., Diesel, P., and Gerlovin, Lev. (2018). New Approaches To Market Access And Reimbursement For Gene And Cell Therapies. Cell & Gene. Retrieved from: https://www.cellandgene.com/doc/new-approaches-to-market-access-and-reimbursement-for-gene-and-cell-therapies-0001

2. Fraser Wright, J. (2014). Product-Related Impurities in Clinical-Grade Recombinant AAV Vectors: Characterization and Risk Assessment. Biomedicines, 2, 80-97; doi:10.3390/biomedicines2010080

3. U.S. Food & Drug Administration (2019). Guidance for Human Somatic Cell Therapy and Gene Therapy. Retrieved from: https://www.fda.gov/animal-veterinary/guidance-industry/chemistry-manufacturing-and-controls-cmc-guidances-industry-gfis

4. Stein, R. (2019). At $2.1 Million, New Gene Therapy Is The Most Expensive Drug Ever. NPR. Retrieved from: https://www.npr.org/sections/health-shots/2019/05/24/725404168/at-2-125-million-new-gene-therapy-is-the-most-expensive-drug-ever

5. Cohen, J.T, Chambers, J. D., Silver, M. C., Lin, P., Neumann, P.J. (2019). Putting The Costs And Benefits Of New Gene Therapies Into Perspective. Health Affairs. Retrieved from: https://www.healthaffairs.org/do/10.1377/hblog20190827.553404/full/

6. ATCC (accessed May, 2020) ATCC Virus Reference Materials. Retrieved from: https://www.atcc.org/en/Standards/Standards_Programs/ATCC_Virus_Reference_Materials.aspx#

7. U.S. FDA (2020). FDA Details Policies on Gene Therapies in Seven Guidances. Retrieved from: https://www.fdanews.com/articles/195767-fda-details-policies-on-gene-therapies-in-seven-guidances

Read more:
Troubleshooting the Development of New Gene Therapies - Technology Networks

XconomyNational

COVID-19 has ravaged the economy, and it was expected to quash the IPO market, too. But the biotech sector is defying the pandemic with crossover financings and freshly minted public companies. On Friday, three firms added their names to the list of life science companies preparing to join the public markets.

Gene therapy company Generation Bio, vaccines developer Vaxcyte, and cancer diagnostics maker Burning Rock Biotech each filed IPO paperwork just ahead of the Memorial Day weekend. The filings come as an index of the largest and most liquid IPOs of the past two years reached an all-time high, according to Renaissance Capital. The IPO research firm says the indexs rise was led by Moderna (NASDAQ: MRNA), the Cambridge, MA-based biotech that this week released preliminary Phase 1 data for its experimental COVID-19 vaccine.

Investors are betting that new technologies and services are best suited for the post-pandemic world, Renaissance says.

Heres a look at the three new additions to the biotech IPO queue.

GENERATION BIO EYES NEXT-GEN GENE THERAPIES

Generation Bio aims to improve upon gene therapy with an alternative to the engineered viruses currently used to ferry these therapies into cells. Viral delivery has limitations that include safety risks and a relatively small genetic payload capacity, the Cambridge-based company says in its filing. Furthermore, if patients dont already have antibodies to the viruses, they develop them after their first dose, which means patients cant receive additional doses if the initial one doesnt work as expected or stops working over time. Gene therapies that employ viral delivery are also expensive to manufacture.

Instead of a virus as its delivery vehicle, Generation Bio uses a lipid nanoparticle. This approach permits an individualized approach to treatment as a patient can be redosed until reaching the level needed for effective treatment, the company says. The technology also has a greater payload capacity and its less expensive to manufacture at scale compared to viral gene therapies. Those differences will enable delivery of gene therapies to more types of tissue, which in turn will allow for the treatment of a broader range of diseases spanning more patients, Generation Bio says.

Generation Bios initial focus is developing gene therapies targeting the liver and the eye. The most advanced liver programs are for for phenylketonuria (PKU), an inherited metabolic disorder, and the bleeding disorder hemophilia type A, the most common form of the bleeding disorder. For the eye, Generation Bio is developing a gene therapy for an inherited form of vision loss called LCA10 and for Stargardt disease, which is a form of macular degeneration.

Generation Bio has raised more than $227 million, most recently a $110 million Series C financing in January. That funding round added crossover investors, whose involvement is viewed as an indication a company is preparing for an IPO. CEO Geoff McDonough acknowledged as much at the time, telling Xconomy he expected to take the company public in advance of beginning clinical trials.

In its filing, Generation Bio set a preliminary $125 million target for its IPO. The company has applied for a Nasdaq listing under the stock symbol GBIO. At the end of the first quarter of this year, Generation Bio reported having $104.5 million in cash. The company says it plans to use the IPO proceeds to continue R&D, including the preclinical work to support an application to start clinical testing of one of its liver disease gene therapies.

Generation Bios largest shareholders are Jason Rhodes, the companys chairman and founding CEO, and Atlas Venture. Each holds a 37 percent pre-IPO stake, according to the filing. Fidelity Investment owns 14.9 percent of the company, followed by funds advised by T. Rowe Price, which hold 8.9 percent.

VAXCYTE SETS SIGHTS ON TOPPING A PFIZER VACCINE

Vaxcyte is the new name for SutroVax, which changed its moniker this week. The Foster City, CA-based company spun out of Sutro Biopharma, and it develops vaccines using technology licensed from its former parent. The company says in its IPO filing that its cell-free protein synthesis technology enables it to design protein carriers and antigensa vaccines key componentsthat are better than what can be produced using conventional vaccine technologies.

Pneumococcal bacteria, which can cause pneumonia and meningitis, are Vaxcytes first target. The top pneumococcal vaccine, a Pfizer (NYSE: PFE) product called Prevnar, is a blockbuster seller that protects against 13 of the more than 90 pneumococcal strains. Vaxcytes preclinical vaccine candidate, VAX-24, is being developed to address 24 strains.

The IPO filing comes two months after Vaxyte closed a $110 million Series D round that added crossover investors. The company says in the filing that it has raised about $282 million cumulatively. As of March 31, Vaxcytes cash holdings totaled $154.7 million. The companys largest shareholders include Abingworth Bioventures, Longitude Capial Management, and Roche Finance, though the percentages of those stakes were not disclosed.

Vaxcyte says it plans to apply for a Nasdaq listing under the stock symbol PCVX. The vaccine developer set a preliminary $100 million goal; proceeds will be used to complete preclinical development and advance VAX-24 into human testing. The cash will also finance manufacturing, as well as continued development of other vaccine candidates.

BURNING ROCK BIOTECH BLAZES A PATH TO NASDAQ

Burning Rock Biotech is based in China, where it sells next-generation sequencing products that help physicians select cancer treatments for their patients. Now its seeking a Nasdaq listing that will give US investors a chance to grab a stake.

The company says in its filing that it offers 13 tests spanning solid tumors including cancers of the lung, prostate, and breast, as well as blood cancers. In addition helping physicians treat cancer patients, Burning Rock says its products support clinical trials conducted by large pharmaceutical companies, including AstraZeneca (NYSE: AZN), Bayer, and Johnson & Johnson (NYSE: JNJ). The companys central laboratory processes biopsy samples from hospital patients as well as from its pharmaceutical partners. The central lab business is the companys largest business segment.

Burning Rock reported $53.9 million in 2019 revenue. For the first quarter of 2020, revenue was $9.5 million. The company set a preliminary $100 million goal for its IPO, and says it plans to apply for a Nasdaq listing under the stock symbol BNR. According to the filing, Burning Rock expects to use the IPO cash for research and development of early cancer detection technologies, as well as for seeking approvals in China for additional cancer therapy selection products.

Image: iStock/peterschreiber.media

Frank Vinluan is an Xconomy editor based in Research Triangle Park. You can reach him at fvinluan@xconomy.com.

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Generation Bio Leads a Trio of Biotech Companies Aiming for the Nasdaq - Xconomy

COVID-19 impact will also be included and considered for forecast.

Global Gene Therapy Market research report provides detail information about Market Introduction, Market Summary, Global market Revenue (Revenue USD), Market Drivers, Market Restraints, Market Opportunities, Competitive Analysis, Regional and Country Level.

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By Type of Vectors Viral vectors Non-viral vectors

By Type of Cells Somatic cells Germline cellsBy Region North Americao U.S.o Canadao Mexico Europeo UKo Franceo Germanyo Russiao Rest of Europe Asia-Pacifico Chinao South Koreao Indiao Japano Rest of Asia-Pacific LAMEAo Latin Americao Middle Easto AfricaGene Therapy Market Key Players: Pfizer Inc. Novartis AG Bayer AG Sanofi GlaxoSmithKline plc. Amgen Inc. Boehringer Ingelheim International GmbH uniQure N.V. bluebird bio, Inc. Celgene Corporation OthersThis comprehensive report will provide: Enhance your strategic decision making Assist with your research, presentations and business plans Show which emerging market opportunities to focus on Increase your industry knowledge Keep you up-to-date with crucial market developments Allow you to develop informed growth strategies Build your technical insight Illustrate trends to exploit Strengthen your analysis of competitors Provide risk analysis, helping you avoid the pitfalls other companies could make Ultimately, help you to maximize profitability for your company.Our Market Research Solution Provides You Answer to Below Mentioned Question: Which are the driving factors responsible for the growth of market? Which are the roadblock factors of this market? What are the new opportunities, by which market will grow in coming years? What are the trends of this market? Which are main factors responsible for new product launch? How big is the global & regional market in terms of revenue, sales and production? How far will the market grow in forecast period in terms of revenue, sales and production? Which region is dominating the global market and what are the market shares of each region in the overall market in 2017? How will each segment grow over the forecast period and how much revenue will these segment account for in 2025? Which region has more opportunities?

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Surveys consistently report that people fear total blindness more than any other disability, and currently the major cause of untreatable blindness is retinal disease. The retina, a part of the brain that extends into the eye during development, initiates vision by first detecting light with the rod and cone photoreceptors. Four classes of retinal neurons then begin the analysis of visual images. Defects in the optical media that transmit and focus light rays onto the retina (lens and cornea) can usually be dealt with surgically, although such treatments are not available in some parts of the world, resulting in as many as 20 to 30 million legally blind individuals worldwide. Untreatable retinal disease potentially causes legal or total blindness in more than 11 million people in the United States alone, but progress in treatments raises the possibility of restoring vision in several types of retinal blindness (1).

Retinal neurons comprise bipolar and horizontal cells, which are second-order neurons that receive signals from the photoreceptors in the outer retina. Third-order amacrine and retinal ganglion cells are activated in the inner retina by bipolar cells. Axons from the ganglion cells form the optic nerve and carry the visual message to the rest of the brain (see the figure). The cells most susceptible to blinding retinal disease are the photoreceptors and ganglion cells. Whereas progress has been made in combating blindness caused by photoreceptor degeneration, little can be done currently to address ganglion cell loss, such as occurs in glaucoma.

The approach that has been most successful in restoring photoreceptor loss that results in complete blindness is the use of retinal prosthetic devices, with two now approved for clinical use (2). These devices electrically stimulate either bipolar or ganglion cells. They require goggles that have a camera that converts visual stimuli into electrical stimuli that activate the device, which in turn stimulates the retinal cells. Several hundred of these devices have been implanted in blind or virtually blind individuals, 70 to 80% of whom report improvement in quality of life. For those who are completely blind, the ability to experience again at least some visual function is viewed as a miracle.

There are substantial limitations to the devices, however. The best visual acuity attained so far is poor (20/500) and visual field size is limited, but many improvements, mainly technical, are being developed and tested, including the potential use of electronic low-vision devices to increase visual field size and acuity (3). Retinal prostheses are not useful for patients who are blind because of loss of ganglion cells and/or the optic nerve, but prostheses that bypass the retina and stimulate more central visual structures, including the lateral geniculate nucleus (the intermediary between retina and cortex) and visual cortex, are being developed and tested in humans (4). There remain considerable technical issues, but preliminary data indicate that such devices are feasible.

A second approach to treat photoreceptor degeneration and potential blindness, now in the clinic, is gene therapy (5). This involves injecting a viral construct into the eye that contains a normal gene to replace an abnormal one. Success so far has been limited to the treatment of Leber congenital amaurosis (LCA) type 2, a rare form of retinitis pigmentosa in which the gene whose product is required to form the correct isomer of vitamin A aldehyde, the chromophore of the visual pigments, is mutated. Little of the correct isomer is made in LCA patients, resulting in substantial loss of photoreceptor light sensitivity. This is reversed when viral constructs encoding the normal gene are injected deep into the eye between the photoreceptors and pigment epithelium.

Two factors make this approach feasible in LCA: The genetic defect is monogenic, and many of the photoreceptors in the patients remain alive, although compromised. Thus, how broadly feasible gene therapy will be for treating the enormous range of inherited retinal diseases now known to exist (300) remains to be seen. But at least a dozen other gene therapy trials on monogenic inherited eye diseases similar to LCA are under way (6). Other methods to manipulate genes are now available, including CRISPR-mediated editing of retinal genes. So far, the experiments have been mainly on isolated cells or retinas, but these powerful techniques are likely to have eventual clinical applications.

A variation on the use of gene therapy techniques is optogenetics, in which light-sensitive molecules are introduced into non-photosensitive retinal cells. This approach holds much promise for restoring vision to totally blind individuals whose photoreceptors have been lost. Using viruses to insert genes encoding light-sensitive molecules into bipolar and ganglion cells, as well as surviving photoreceptor cells that are no longer photosensitive, has been accomplished in animals and shown to restore some vision (7). Again, technical issues remain: The cells made light-sensitive require bright light stimuli, and the light-sensitive cells do not adapt. That is, whereas photoreceptors normally allow vision over as much as 10 log units of light intensity, the cells made light-sensitive respond only to a range of 2 to 3 log units. Various methods to overcome these limitations are now being developed, and at least one clinical trial is under way. Experiments to make cortical neurons sensitive to light or other stimuli that better penetrate the skullmagnetic fields or ultrasound, for exampleare also being developed and tested in animals.

Other promising approaches to restore vision are being explored. In cold-blooded vertebrates, retinal cells (in fish) and even the entire retina (in amphibians) can regenerate endogenously after damage. Regeneration of retinal cells in zebrafish is now quite well understood (8). The regenerated neurons come from the major glial cell in the retina, the Mller cell. After retinal damage, Mller cells reenter the cell cycle and divide asymmetrically to self-renew and produce a progenitor cell that proliferates to produce a pool of cells capable of differentiating into new retinal cells that repair the retina.

A number of transcription factors and other factors identified as being involved in retinal regeneration in zebrafish have been shown to stimulate some Mller cell proliferation and neuronal regeneration in mice. Regenerated bipolar and amacrine cells, as well as rod photoreceptors, have so far been identified in mouse retinas, and these cells are responsive to light stimuli (9, 10). Further, cells postsynaptic to the regenerated neurons are activated by light stimuli, indicating that the regenerated neurons have been incorporated into the retinal neural circuitry. So far, the regenerative capacity of mammalian Mller cells is limited, but directed differentiation of specific types of neurons with a mix of factors appears to be a possibility. Regrowth of ganglion cell axons after the optic nerve is disrupted is also under active investigation, and although the number of axons regrowing is low (10%), those that do regrow establish synaptic connections with their correct targets (11). Therefore, endogenous regeneration is still far from clinical testing, but substantial progress has occurred.

The retina lines the back of the eye and consists of rod and cone photoreceptors, as well as four types of neuron: second-order bipolar and horizontal cells and third-order retinal ganglion cells (RGCs) and amacrine cells. Mller glial cells fill the spaces between the neurons. The pigment epithelium, critical for photoreceptor function, underlies the retina. Photoreceptors and RGCs are most susceptible to blinding retinal disease. Progress in combating photoreceptor degeneration has been made, but there are few strategies to address RGC loss.

A long-studied area of research is transplantation of retinal cells, particularly photoreceptors, into diseased retinas. In experiments with mice, transplanted postmitotic rod photoreceptor precursor cells derived from embryonic retinas or from stem cells appeared to integrate into diseased retinas in reasonable numbers and to be functional. A surprising and unexpected complication in the interpretation of these experiments was recently discovered. Rather than integrating into diseased retinas, the donor cells appear to pass material (RNA or protein) into remaining host photoreceptor cells, rejuvenating them, and these appear to be most of the functional cells (12). The current evidence suggests that only a small proportion of the donor cells integrate, but progress in overcoming this setback is being made.

More success has been reported with stem cells induced to become pigment epithelial (PE) cells, which provide essential support for photoreceptors. A number of blinding retinal diseases relate to the degeneration of the PE cells, and replacement using such cellsin a suspension or on a scaffoldis being actively pursued. PE cells do not need to integrate synaptically with retinal cells; they simply need to contact the photoreceptor cells. This is achieved when PE cells are placed between the retina and the back of the eye. Early clinical trials suggest that the transplants are safe, but retinal detachment, a serious complication, can occur and efficacy has yet to be shown (13).

The finding that donor photoreceptor cells can help diseased host retinal cells to recover function suggests that certain substances can provide neuroprotection. Indeed, a substantial number of such neuroprotective molecules have been shown to affect retinal disease progression, especially degeneration of photoreceptor cells. No one factor has been shown to be effective generally, but two have received much attention. One, ciliary neurotrophic factor (CNTF), promotes photoreceptor survival in light-induced photoreceptor degeneration and in several other models of retinal degeneration (14). Some evidence suggests that CNTF acts primarily on Mller cells, but how it works, and on what cells, is still unclear. The other factor, rod-derived cone viability (RDCV) factor, has received less research attention, but with recent industrial support, it is now being advanced to the clinic. Current evidence indicates that RCDV factor protects cones after rod degeneration.

Two of the most common retinal diseases in developed countriesage-related macular degeneration (AMD), the leading cause of legal blindness (visual acuity of less than 20/200), and glaucoma, the leading cause of total blindnessare not monogenic diseases, and so genetic treatments for them are not obvious. Attempts to understand the etiology of these diseases are under way, but currently their underlying causes are still unclear. A difficulty presented by AMD is that no animal model is readily available, because it is a disease of the fovea, which mediates high-acuity vision. Except for primates, other mammals do not possess this small critical retinal area. Whereas large primates are not feasible for extensive cellular or molecular studies, small primates such as marmosets that have a fovea are potential models but have not been used much to date.

Other approaches for restoring vision have been suggested and have even yielded some progress. From both normal humans and those with an inherited retinal disease, skin biopsy cells can be induced to form tiny retinal eyecups called organoids (15). Containing all retinal cell types, these structures could be a source of retinal cells for studying retinal disease development and possible therapies, as well as for cell transplantation. A fovea has not been observed in any organoid so far, but this is not beyond the realm of possibility. Another suggested approach is to surgically transplant whole eyes into blind individuals. This appears feasible, but whether there is sufficient optic nerve regrowth remains an open question.

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Restoring vision to the blind - Science Magazine

Applied Genetic Reports Positive Preclinical Data for Eye Disorder Treatment

Applied Genetic Technologies Corporation (NASDAQ:AGTC) announced the results for its clinical trial related to X-Linked retinitis pigmentosa. The data provided the basis for determining the starting dose and the vector for its current Phase 1/2 clinical trial. The results demonstrated that the company's proprietary AAV vector and engineered RPGR constructs were well tolerated. It also had a positive impact on markers of disease in a canine model of XLRP.

Full length RPGR protein's DNA sequence may contain repetitive sequences which may cause instability during vector engineering and manufacturing. There are two main approaches in this regard. The first one involves removing the repetitive sequence, leading to a shortened RPGR protein while another approach is to cut down instability while producing the full length RPGR protein. Mark S. Shearman, Ph.D., Chief Scientific Officer, AGTC, said, "The results of this study identified an AAV-RPGR vector construct that has optimized safety and efficacy in a highly relevant animal model of human XLRP disease and that large-scale manufacturing that will be essential for making XLRP gene therapy available to the patients who may benefit from it." The company had earlier reported positive interim six-month data from Phase 1/2 XLRP clinical trial.

This dose ranging study used the company's proprietary rAAV2tYF capsid to deliver either a truncated RPGR DNA sequence (hRPGRstb) or an RPGR sequence encoding full-length RPGR protein optimized for stability (hRPGRco) in a canine model of XLRP. After subretinal injection, both transgenes showed similar levels of efficacy. The variables used for this purpose included fundus reflectivity, outer nuclear layer thickness, correction of opsin mislocalization and length of cone inner segments. However, in some cases, hRPGRco showed superior performance. Both the vectors were well tolerated. High dosage group experienced some cases of inflammation and retinal detachment.

Gilead Sciences, Inc. (NASDAQ:GILD) announced positive top-line data from its Phase 2b/3 trial designed to assess the efficacy and safety of filgotinib in biologic-nave or biologic-experienced adult patients with moderately to severely active ulcerative colitis. The drug candidate met all its primary endpoints at 200mg dosage. However, at 100mg dosage, it did not show any statistically significant clinical remission at Week 10.

The results were obtained from SELECTION, a Phase 2b/3, double-blind, randomized and placebo-controlled trial. It involved 1,348 patients being administered oral, once-daily, selective JAK1 inhibitor drug candidate. At week 10, the drug showed clinical remission, which is defined as an endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and 1 point decrease in stool frequency from baseline to achieve a subscore of 0 or 1. In the biologic-nave cohort, 52 percent of patients had nine or higher on a baseline Mayo Clinic Score (MCS) while the corresponding ratio for biologically-experienced cohort stood at 74 percent.

For biologic nave patients cohort, 26.1 percent of the patients showed clinical remission at Week 10 when treated with filgotinib 200 mg in comparison to 15.3 percent hitting the mark in placebo group. The corresponding data for biologic-experienced patients was at 11.5 percent and 4.2 percent, respectively. Both the cohorts showed statistically significant better performance. Patients who showed either a clinical response or remission after 10 weeks of treatment with filgotinib 100 mg or 200 mg were re-randomized to their induction dose of filgotinib or placebo in a 2:1 ratio and treated through Week 58. For the maintenance trial, both the doses met their primary endpoints.

For biologic nave patients, in the induction trial, 1.2 percent patients showed serious adverse events for 200mg dosage, while 4.7 percent suffered these hazards at 100mg dosage. The corresponding data for placebo group stood at 2.9 percent. Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences said, "Patients with moderate to severe ulcerative colitis can struggle to effectively manage their disease. These top-line data suggest that filgotinib could play a role in helping more patients achieve a meaningful and sustained improvement in treatment response with an oral therapy." Ulcerative colitis is a chronic and idiopathic inflammatory disease.

The SELECTION Phase 2b/3 trial is a multi-center, randomized, double-blind, placebo-controlled trial. It comprised two induction trails and a Maintenance Trial. The company is collaborating with Galapagos NV (NASDAQ:GLPG) for developing and commercializing filgotinib in various inflammatory indications. Some of the other clinical trials involving the drug candidate are the DIVERSITY Phase 3 trial in Crohn's disease, the FINCH Phase 3 program in rheumatoid arthritis and the Phase 3 PENGUIN trials in psoriatic arthritis. It is also being tested in Phase 2 studies in uveitis and in small bowel and fistulizing Crohn's disease.

Filgotinib is a lead drug candidate for Gilead and is an investigational agent. The drug candidate is currently under review by the FDA as treatment for rheumatoid arthritis. It is also being reviewed in other geographies including European Union. The drug is expected to face competition from the likes of Rinvoq from AbbVie (NYSE:ABBV) but is still likely to generate impressive revenue stream. Since the drug failed to meet its primary endpoint at 100mg dosage, the prospects for 200mg dosage seem better.

Apellis Pharmaceuticals Inc. (NASDAQ:APLS) announced that it is in the process of submitting a New Drug Application (NDA) for pegcetacoplan during the second half of 2020. The application will be accompanied by the data from the Phase 3 PEGASUS trial comparing pegcetacoplan to eculizumab in patients suffering from Paroxysmal Nocturnal Hemoglobinuria. The company is also in the process of carrying out discussions with authorities in the European Union.

The PEGASUS study is a randomized, multi-center, active comparator and open label controlled Phase 3 study. The trial involved 80 adult patients suffering from Paroxysmal Nocturnal Hemoglobinuria. The primary endpoint of the trial was to assess the efficacy and safety of pegcetacoplan compared to eculizumab. Participants were required to be on eculizumab (stable for at least three months) with a hemoglobin level of <10.5 g/dL at the screening visit. All participants completing the randomized controlled period proceeded to the open-label pegcetacoplan treatment period. They were administered pegcetacoplan in the randomized and controlled period.

The study met its primary endpoint as the data showed superior performance by pegcetacoplan to eculizumab. The drug candidate led to a statistically significant improvement in hemoglobin levels at 16 weeks. During the run-in period of four weeks, the participants were given 1080 mg of pegcetacoplan twice a week along with their current dose of eculizumab. For 16-week randomized, controlled period, the participants were randomized and they were either given their current dose of eculizumab or 1,080 mg of pegcetacoplan twice weekly. The data also showed that pegcetacoplan had the drug safety profile comparable to eculizumab.

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Applied Genetic Reports Positive Data, And Other News: The Good, Bad And Ugly Of Biopharma - Seeking Alpha