Impressive Returns on $70 Million Translational Research Investment

December 20, 2013

Eighteen of the world’s leading retinal researchers convened in Las Vegas November 18-20 to present their progress in advancing clinically focused research made possible by the Foundation’s Translational Research Acceleration Program (TRAP). Since 2008, $70 million has been allocated to the program to move promising retinal-disease treatments into human studies.

A major goal of TRAP is to develop therapies to the point where they attract outside investment from biopharmaceutical companies and venture capital firms, which have the financial resources necessary for supporting clinical trials that lead to commercial availability of treatments. One case in point is an optogenetic treatment now being developed by GenSight Biologics, a French gene-therapy development company. Thanks, in part, to the promise of this TRAP-funded therapy — designed to restore vision for people with advanced retinitis pigmentosaJosé Sahel, M.D., and his GenSight collaborators have garnered venture-capital funding.

“We are delighted by the commercial investment being attracted to TRAP-funded research,” says Gordon Gund, chairman and co-founder of the Foundation and a lead TRAP investor. “These partnerships are providing the capital and development expertise needed to get human studies off the ground.”

“Our researchers are innovators with great ideas that have strong potential for saving vision. Industry is recognizing that fact and eager to include TRAP-funded projects in their portfolios,” says Stephen Rose, Ph.D., chief research officer of the Foundation.

TRAP currently funds a broad range of research projects, including stem cells, gene therapies, pharmaceuticals, gene discovery and knowledge-advancing clinical and genetic studies. Most of the projects involve emerging therapies that are two to five years away from human studies.

Listed below are overviews and statuses of TRAP-funded projects:

Gene Therapies: Thanks to the early success of several gene-therapy clinical trials for retinal diseases, the Foundation has made gene therapy a major part of its translational research program. A key benefit of gene therapy is that a single dose may halt disease progression and last several years or perhaps a lifetime. Many retinal-disease gene therapies involve the delivery of a normal gene to replace or correct a defective, disease-causing gene.

Gene Therapy for X-Linked Retinoschisis
In collaboration with a Foundation-funded research team at Oregon Health & Science University, Applied Genetic Technologies Corporation (AGTC) is developing a gene therapy based on an adeno-associated virus (AAV) for X-linked retinoschisis (XLRS). Jeff Chulay, M.D., vice president and chief medical officer of AGTC, said the company’s goal is to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration in late 2014 and begin a clinical trial in 2015. Formal safety studies in small and large animal models required for IND submission will begin shortly.

A natural-history study of people with XLRS has also been initiated to identify the best measures for evaluating treatment efficacy. In 2012, the company received $37.5 million in venture-capital funding. The Foundation funded earlier lab research to advance XLRS gene therapy development and attract venture-capital support for AGTC.

Gene Therapy for LCA1 (GUCY2D mutations)
Investigators from the Universities of Pennsylvania and Florida have demonstrated efficacy for gene therapy in two mouse models of Leber congenital amaurosis type 1 (LCA1) — one rich in cones, the other rich in rods. Based on an adeno-associated virus, the treatment provided profound improvement in vision, which has persisted for eight months thus far. Patients with LCA1 have also been identified and characterized in preparation for a human study.

Additional lab studies, including those for safety, are also planned to gain authorization from the U.S. Food and Drug Administration to launch a clinical trial. A partnership with a pharmaceutical company is also being explored. The investigative team includes: Samuel Jacobson, M.D., Ph.D., University of Pennsylvania; William Hauswirth, Ph.D., and Shannon Boye, Ph.D., University of Florida; and Alexander Dizhoor, Ph.D., Salus University.

Gene Therapy for Autosomal Dominant Retinitis Pigmentosa
Gene therapies for autosomal dominant retinal diseases can be more challenging to develop than those for autosomal recessive conditions, because they may require a two-step process: knock down the mutated gene and replace it with a normal gene. Al Lewin, Ph.D., and William Hauswirth, Ph.D., of the University of Florida, are evaluating two different knock-down approaches for a treatment for autosomal dominant retinitis pigmentosa (adRP) caused by mutations in RHO.

One uses a ribozyme, an enzyme that can be engineered to act like a molecular scissors. It shuts down the production of mutant RHO by snipping the deleterious RNA into pieces. The other technique employs short-interfering RNA (siRNA), which trick a gene-silencing machine already in the cell into degrading the mutant RNA. Drs. Lewin and Hauswirth are also developing a one-step approach for treating some forms of adRP. Simply overriding the mutant gene with a healthy gene might also work in some cases.

Read more about this research.

Gene Therapy for LCA6 (RPGRIP1 Mutations)
A research team from Massachusetts Eye and Ear Infirmary — which includes Basil Pawlyk, Ph.D., Eliot Berson, M.D., and Luk Vandenberghe, Ph.D. — is developing a gene therapy based on an adeno-associated virus for Leber congenital amaurosis (LCA) caused by RPGRIP1 mutations. An earlier studied showed that gene therapy rescued degenerating rods and cones in a mouse model of the condition.

Forthcoming studies will determine if the therapy is effective for both early- and late-stage disease. Researchers will also perform toxicology studies in mice and large animals in preparation for submission of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration for authorization to launch a clinical trial.

Gene Correction Therapy for Usher Syndrome Type 1C
Jennifer Lentz, Ph.D., of Louisiana State University, recently received TRAP funding to develop a therapy for saving and/or restoring vision in people with the 216A gene mutation — a defect prevalent in the Acadian population — which causes Usher syndrome type 1C. Known as an antisense-oligonucleotide (ASO), the therapy is a small piece of genetic material designed to correct mutant RNA, which are the genetic messengers leading to the production of critical proteins. Previously, she and her colleagues showed that the approach corrected deafness and balance problems in Usher 1C mice.

Dr. Lentz also plans to design an ASO therapy for other mutations that cause Usher 1C. Her collaborators for the project are Michelle Hastings, Ph.D., co-principal investigator, of Rosalind Franklin University of Medicine and Science, and Frank Rigo, Ph.D., at Isis Pharmaceuticals.

Gene Therapies for Autosomal Recessive Retinal Diseases
Ed Stone, M.D., Ph.D., and his colleagues at the University of Iowa recently received TRAP funding to gain a better understanding of the mechanisms of autosomal recessive retinal diseases and develop gene therapies for them. His team will take skin and blood samples from patients, turn them into stem cells, and then coax them into becoming retinal cells. Known as induced pluripotent stem cells (iPSC), they will be used to study how degeneration occurs and efficacy of potential gene therapies.

The team will study gene therapy delivery systems based on adeno-associated viruses, lentiviruses and the herpes simplex virus. Dr. Stone’s identification of the gene MAK as a cause of autosomal recessive retinitis pigmentosa in Ashkenazi Jews — and characterization of the condition in patient-derived iPSC — is a recent success of his lab. His team is now focused on advancing gene and stem-cell therapies for MAK-associated disease into human studies.

Increasing Cargo Capacity for AAV-Based Gene Therapies
Many replacement genes for retinal diseases — including CEP290, USH2A, CRB1, MYO7A, and RP1 — exceed the cargo capacity of human-engineered viruses designed to deliver them to retinal cells. Luk Vandenberghe, Ph.D., of Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, is exploring two approaches to overcoming this challenge, both of which use adeno-associated viruses (AAVs).

One involves delivery of the gene in two parts, which recombine in the targeted cells. The other approach involves the generation of millions of variations of the AAV’s gene-packaging system to find one that can accommodate a gene that’s too large for the normal AAV-packaging system. He is currently studying these approaches in a dish (in vitro) and in mouse models with the plan of moving his research to larger animals and, eventually, into human studies.

Increasing Cargo Capacity of Gene Therapies through Directed Evolution
Because increasing gene delivery capacity is critical for the development of gene therapies for several retinal diseases, the Foundation is also funding  David Schaffer, Ph.D., of the University of California, Berkeley, to address the need. He’s using a process known as directed evolution, a form of random generation, to create millions of AAV variants to find one that can effectively deliver large genes to the retina. Dr. Schaffer and his team have conducted multiple rounds of directed evolution and are analyzing promising variants that have emerged from the process.

Optogenetics: The Foundation funds several optogenetic research projects because of their potential to restore vision in people with the most advanced retinal diseases. The new, quickly advancing treatment approach involves the delivery of genes or compounds that bestow light sensitivity to cells in the retina. Different retinal cell types may be targeted for a treatment, depending on the underlying disease and severity.

Reactivating Cones, Restoring Vision through Optogenetics
In many patients with advanced forms of retinitis pigmentosa (RP), their cones, the retinal cells that provide central and daylight vision, go into a dormant state; they remain alive but no longer provide vision. José Sahel, M.D., of the Institut de la Vision in Paris, is developing a gene therapy based on an adeno-associated virus that reactivates dormant cones to restore vision. A key benefit of this optogenetic treatment is that it should work regardless of which gene mutation is causing the RP.

The treatment leads to the production of a protein known as halorhodopsin, which renders the cones light-sensitive, thereby restoring vision. Thus far, Dr. Sahel’s team has shown efficacy in a mouse model and human retinal tissue. They are now optimizing the treatment in a large animal model. Their goal is to launch a clinical trial in 2015.

Read more about this research.

Optogenetic Therapy that Restores Vision by Activating Bipolar Cells
John Flannery, Ph.D., at the University of California, Berkeley, recently received funding to develop an optoegentic gene therapy. Based on an adeno-associated virus, it is designed to restore vision in people with advanced retinal diseases which have led to total loss of photoreceptors. The treatment works by delivering a light-sensing molecule to bipolar cells in the retina, which survive after photoreceptors have been lost.

Four different molecules will be evaluated in mice and canine models of retinal degeneration. Behavioral studies will be performed to determine if (and how well) vision is being restored. The treatment should work independent of the patient’s disease-causing gene mutation.

Optogenetic Small Molecule for Restoring Vision
Richard Kramer, Ph.D., of the University of California, Berkeley, recently received funding to develop an optogenetic small molecule for restoring vision in people who have lost all of their photoreceptors to advanced inherited retinal diseases, such as retinitis pigmentosa. He has identified a lead molecule known as DENAQ for conferring light sensitivity to retinal ganglion cells, which survive after photoreceptors are lost to disease.

Dr. Kramer believes that DENAQ might also be beneficial for people with central vision loss from advanced age-related macular degeneration, if it can be targeted to ganglion cells in the central retina. The advantage of an optogenetic small molecule over an optogenetic gene therapy is that dosing can be modulated — increased, decreased or discontinued — depending on the effects on the patient. In an early study, Dr. Kramer has shown that a single dose of DENAQ can work for several days or possibly weeks.

Stem Cells: The Foundation is committed to advancing stem-cell research for replacing retinal cells that are lost in people with a wide range of advanced retinal diseases. Stem cells hold promise for restoring vision in people who are completely blind or with extensive vision loss. The Foundation funds research for different types of stem cells, because each has its own advantages and limitations.

Multi-Layered Patch for Restoring Vision in People with Advanced Retinal Disease
In many retinal degenerative conditions — including Stargardt disease, age–related macular degeneration, and choroideremia — two types of cells are lost: photoreceptors, which make vision possible, and retinal pigment epithelial (RPE) cells, which provide waste removal and nutritional support for photoreceptors. David Gamm, M.D., Ph.D., at the University of Wisconsin-Madison, is leading a team in the development of a vision-restoring retinal patch comprised of photoreceptor precursors and RPE cells. Dennis Clegg, Ph.D., of the University of California, Santa Barbara, is developing a scaffold to provide structural support for the cells.

A biodegradable gel will be used to hold the layers of the patch together. The photoreceptor precursors and RPE cells will be derived from induced pluripotent stem cells (iPSC) obtained from small skin or blood samples from human donors. The cells for clinical trials will be produced by Cellular Dynamics International under the guidance of Derek Hei, Ph.D., an expert in the biomanufacturing industry standard known as Good Manufacturing Practices (GMP). Jamie Thomson, Ph.D., V.M.D., who discovered embryonic stem cells in 1997, and co-identified iPSC in 2007, is also a member of the team.

Developing Retinal Disease Therapies from Human Embryonic Stem Cells
Thomas Reh, Ph.D., of the University of Washington, has shown that human embryonic stem cells (hESC) can be used to make photoreceptors. He and his colleagues have achieved some initial success in transplanting hESC-derived therapies into a variety of animal models. In particular, they have shown that the transplanted cells have not caused major safety issues (e.g., no rejection from the immune system). He and his colleagues are now working to increase long-term survival of the transplanted cells and restoration of visual function. The team is also seeking a commercial partner for a future clinical trial.

Drugs and Small Molecules: The Foundation is funding the development of several vision-saving drugs with the goal of maximizing the number that will be commercialized and made widely available. Drugs taken as pills or eye drops have many potential advantages in treating retinal diseases. They may slow vision loss for a broad range of conditions, independent of the underlying genetic cause of disease. Also, dosing can be easily increased or decreased, based on the needs of the patient.

Emerging Drug Shows Strong Vision-Saving Potential
Established by TRAP-funded scientists Bärbel Rohrer, Ph.D., and Craig Besson, Ph.D., the company MitoChem Therapeutics is developing a small molecule to boost mitochondrial function, and preserve vision, in people with a broad range of retinal diseases. Mitochondria are power supplies for all cells and play a key role in cell survival. The idea is to keep mitochondria healthy, so they can provide the needed energy to keep diseased retinal cells working.

After screening 50,000 compounds — and identifying and refining the most attractive therapeutic candidates — the scientists are advancing a molecule known as CB11 toward human studies. CB11 has had a powerful vision-saving effect in preliminary lab studies. Early indications are that the drug may be delivered as an eye drop. Additional large-animal studies will be performed shortly to verify safety, efficacy and the optimal method of delivery.

Developing Neuroprotective Molecules for Treatment of Retinal Degenerations
After screening more than 15,000 molecules, Don Zack, M.D., Ph.D., of Johns Hopkins University, identified the cancer drug sunitinib as a promoter of photoreceptor survival in animal and lab models of retinal disease. He is now developing a test to find similar molecules which are more potent and have fewer off-target effects.

Dr. Zack’s initial work was greatly accelerated through a partnership with the National Institute of Health’s Chemical Genomic Center, which provided state-of-the-art, high-throughput technology for screening potential therapeutic candidates. He also receives funding from BioMotiv, a company focused on accelerating breakthrough discoveries from research institutions into therapies for patients. Matt LaVail, Ph.D., of the University of California, San Francisco, is conducting animal studies in support of the project.

Screening Potential Therapies in Zebrafish
Jeff Mumm, Ph.D., at Johns Hopkins University, is screening drugs already approved by the U.S. Food and Drug Administration in a zebrafish model of retinal disease. He’ll be using technology that enables screening of tens of thousands of drugs weekly. He notes that previous drug screens at this throughput level were usually done with cells in a Petri dish, which was a far less accurate testing approach; initial drug candidates often failed when subsequently screened in animal models. His testing protocol will assess rod photoreceptor survival.

Read more about this research.

Genetic Discovery: Identifying the genes and mutations that lead to retinal diseases provides diagnoses for patients as well as targets for potential therapies. Thanks in part to Foundation funding and advancing screening technologies, more than 200 retinal disease genes have been discovered thus far, but dozens, perhaps hundreds, more have yet to be identified.

Targeted High-Throughput Sequencing for Gene Discovery of Autosomal Dominant RP
A team led by Stephen Daiger, Ph.D., of the University of Texas Health Science Center, is using next-generation, massively parallel DNA sequencing methods to identify genes and mutations causing autosomal dominant retinitis pigmentosa (adRP). Dr. Daiger said that prior to the study, it was possible to identify disease-causing mutations in about 50 to 60 percent of adRP families. Using advanced technologies, he can find the cause in 70 percent. Genetic diagnoses give patients more opportunities for participating in current and future clinical trials. His work is also leading to discovery of new adRP-associated genes (e.g., RPE65, which was already known to cause recessive RP and Leber congenital amaurosis).

Clinical Trial Endpoints: With more human studies for retinal-disease treatments being launched every year, the need for clinical-trial endpoints is now paramount. Endpoints can show that a therapy is working more quickly than standard vision tests can. The Foundation is committed to funding research to identify endpoints that can be used freely and broadly by researchers and therapy-development companies.

Developing Surrogate Outcome Measures for Clinical Trials
Because vision loss for many people with inherited retinal disease progresses slowly — over several years or decades — it can take a considerable amount of time and money to determine if a potential therapy is saving vision in a clinical trial. Hendrik Scholl, M.D., of Johns Hopkins University, is using high-tech retinal imaging systems to identify clinical trial endpoints that can more quickly determine a therapy’s effect. Surrogate endpoints that correlate changes in retinal structure with vision changes are a valuable resource in human studies, because they can significantly reduce the time and cost to demonstrate that a treatment is working.

Dr. Scholl is evaluating technologies such as confocal scanning laser ophthalmoscopy, optical coherence tomography and microperimetry for identifying potential surrogate endpoints. His ultimate goal is to identify those that can be validated by the U.S. Food and Drug Administration for use in clinical trials and commercial approval of therapies. Dr. Scholl is also the principal investigator for ProgSTAR, a Foundation-funded study of the progress of Stargardt disease in people. The primary goal of the study is to identify endpoints for clinical trials of potential therapies.