Several FFB-Funded Treatments Moving Closer to Human Studies

December 22, 2014
A few weeks ago, 15 of the world’s leading retinal researchers, all funded by  FFB’s Translational Research Acceleration Program (TRAP), gathered for an annual meeting in Las Vegas to discuss their progress in developing vision-saving treatments. Most are poised to move into clinical trials within the next two to five years.  
“It’s an exciting time in translational research for retinal diseases,” says Patricia Zilliox, Ph.D., chief drug development officer at the Foundation’s Clinical Research Institute.  “Since 2007, more than a dozen emerging therapies have moved into human studies, and TRAP continues to position us well to expand that number significantly in the next few years, and we and our researchers are working tirelessly to make these clinical studies happen. That’s important, because people affected by retinal diseases are depending on us.”
Since launching the program in 2008, the Foundation has invested more than $70 million in TRAP, which focuses on translational research for moving emerging therapies out of the laboratory and into human studies. It’s a process that presents formidable technical and financial challenges. 
“Translational research is expensive, because it requires costly safety studies and the production of therapies that meet high regulatory standards for evaluation in humans,” says Stephen Rose, Ph.D., chief research officer at the Foundation. “Also, there’s risk — not all projects make it through the process successfully,” The U.S. Food and Drug Administration (FDA) rightfully sets a high bar for safety to protect the patients, and it is incumbent upon us and our researchers to make the investments to meet those requirements.”
TRAP supports a variety of research initiatives, including stem cells, gene therapies, and pharmaceuticals. 
Listed below are summaries of the status updates, by research type, provided by the TRAP-funded scientists in Las Vegas:
Optogenetics and Optopharmaceuticals: Though these treatment approaches have only been in research labs for the last few years, they hold great potential for restoring vision in people who have lost most or all of their vision from retinal diseases. It involves the delivery of a gene or drug to bestow light sensitivity to surviving cells in an affected retina that no longer provides vision. Optogenetic and Optopharmaceutical treatments have potential to help people who are completely blind from diseases such as retinitis pigmentosa.
Resurrecting Cones for Restoring Vision 
Sophisticated retinal imaging studies have revealed that diseased cones, the photoreceptor cells that enable people to perceive detail and see in lighted conditions, often go into a dormant state even if they no longer provide vision. That makes them a good target for an optogenetic therapy. José Sahel, M.D., at the Institut de la Vision in Paris, is developing an optogenetic treatment that uses an adeno-associated virus to deliver a light-sensitive gene called halorhodopsin to cones, rendering them light-sensitive, thereby restoring vision. A key benefit of this optogenetic treatment is that it should work regardless of the gene mutation causing the disease. Dr. Sahel’s team has shown efficacy in a mouse model and human retinal tissue. They are currently conducting toxicology studies and producing a therapy that is suitable for study in humans. Their goal is to seek regulatory authorization to launch a clinical trial in late 2015.
Optogenetic Therapy Restores Vision by Harnessing Bipolar Cells
After evaluating several optogenetic therapy options in mice, John Flannery, Ph.D., at the University of California, Berkeley, and his colleagues are advancing a treatment that leads to the production of a light-activating protein known as a light-gated ionotropic glutamate receptor or LiGluR. Dr. Flannery believes bipolar cells, which survive after photoreceptors are lost, are a good target for the vision-restoring therapy. He is currently collaborating with researchers at the University of Pennsylvania to test the treatment in canine models of retinal degeneration. Success in large animal models is an important step toward gaining authorization to launch a clinical trial. The treatment should work independent of the patient’s disease-causing gene mutation.
Optopharmaceutical Small Molecule for Restoring Vision
When Richard Kramer, Ph.D., of the University of California, Berkeley, began his TRAP-funded research, he was working with a promising chemical called DENAQ, which conferred light sensitivity to ganglion cells in mice. That put him on a path of developing the chemical for restoring vision in people who have lost all of their photoreceptors to advanced inherited retinal diseases, such as retinitis pigmentosa. Since achieving that initial milestone, he has discovered that a related chemical known as BENAQ may work even better. It persists in the retina for 21 days — three times longer than DENAQ. And, it is 100-times more potent than DENAQ.  The advantage of an optopharmaceutical treatment over an optogenetic gene therapy is that dosing can be modulated — increased, decreased or discontinued — depending on the effects on the patient. Though Dr. Kramer is still about three years from being ready for a human study, he has had some initial conversations about BENAQ clinical development with the FDA.   
Gene Therapies: Gene replacement therapies — replacing bad copies of the gene with good — are a promising treatment approach for inherited retinal diseases, because the conditions are caused by mutations in only one gene and the retina is an accessible target for treatment delivery. Furthermore, they are performing safely and restoring vision in several retinal-disease human studies.
Gene Therapy for X-Linked Retinoschisis (XLRS)
In collaboration with a Foundation-funded research team at Oregon Health & Science University, Applied Genetic Technologies Corporation (AGTC) is on track to begin a clinical trial for its XLRS gene therapy in 2015. AGTC is completing the final lab study necessary for seeking FDA authorization for launching the human trial. It has also identified 43 study participants and is developing the clinical trial protocol. 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 are about two years from launching a gene-therapy clinical trial for people with Leber congenital amaurosis type 1 (LCA1). The researchers have determined the optimal location in the retina for delivering the treatment, and they’ve identified 58 potential clinical trial participants.  Additional lab studies, including those for safety, are planned to gain authorization from the FDA to launch the clinical trial. The scientists are partnering with the pharmaceutical company Genzyme, which has invested $900,000 in the project.
Gene Therapy for LCA6 (RPGRIP1 Mutations)
A research team from the Massachusetts Eye and Ear Infirmary, which includes Basil Pawlyk, Ph.D., and Luk Vandenberghe, Ph.D., has overcome a significant challenge in its development of an LCA6 gene therapy. For several months, they had great difficulty getting the treatment to work in mice with LCA6. They ultimately determined that the therapeutic gene was slightly oversized, and did not fully fit into the adeno-associated virus, or AAV, which is used to deliver the gene to retinal cells. As a result, many of the viral particles contained only a fragment of the treatment gene. However, the treatment gene underwent re-development resulting in a complete gene that easily fits into the AAV, and rescues degenerating rod and cone photoreceptors in the LCA6 mouse model. The investigators hope to gain FDA authorization to launch the clinical trial in 2017.
Gene Correction Therapy for Usher Syndrome Type 1C
Jennifer Lentz, Ph.D., at Louisiana State University, has received a three-year grant to develop a gene-correction therapy for saving and/or restoring vision in people with Usher syndrome type 1C caused by the 216A gene mutation, a defect prevalent in the Acadian population. 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. The treatment has corrected hearing and balance problems in Usher 1C mice. In the first year of the grant, Dr. Lentz has determined the optimal dose for producing the correct amount of Usher 1C protein. Her next step is to evaluate the effect of the dose on vision in the mice. Dr. Lentz is also considering using induced pluripotent stem cells (iPSC) — stem cells derived from a patient’s skin or blood — as a human model for testing the safety and efficacy of the ASO therapy. In the later stages of the project, she plans to develop an ASO therapy for other mutations that cause Usher 1C. 
Gene Therapies for Recessive Retinal Diseases (CEP290, MAK, ABCA4 Mutations)
Ed Stone, M.D., Ph.D., and his colleagues at the University of Iowa are using iPSC and mouse models to better understand autosomal recessive retinal diseases — specifically retinitis pigmentosa (MAK mutations), Leber congenital amaurosis (CEP290 mutations), and Stargardt disease (ABCA4 mutations) — and evaluate related gene therapies for saving and/or restoring vision. Over the past year, the Stone lab has been able to use gene therapies to correct the genetic defects in iPSC derived from patients with MAK- and CEP290-linked disease. Correcting the disease in mice is their next step. They hope to launch human studies in the next two years.
Saving Rods and Preserving Cones with Gene Therapies
Concentrated in the central retina, cones are the photoreceptors most critical to our independence and daily activities, because they enable us to perceive details (e.g., read) and colors, and see in lighted conditions.  José Sahel, M.D., and his colleagues at the Institut de la Vision in Paris, discovered that certain proteins secreted by rods, the photoreceptors that provide peripheral vision and the ability to see in dark settings, are critical to the survival of cones. Dr. Sahel’s team is developing a gene therapy that provides sustained release of these proteins, aptly named rod-derived cone viability factors (RdCVFs), to save vision in people with retinitis pigmentosa and potentially other retinal conditions. In particular, the protein RdCVF2 has shown strong cone preservation in a mouse model of autosomal recessive retinitis pigmentosa, and is currently being studied in an autosomal dominant mouse model of RP. If successful, clinical trial preparation will follow.
Stem Cells: Stem cells hold strong potential for restoring vision in people who are completely blind or with advanced vision loss, because they can be used to grow new photoreceptors to replace those lost to disease. The Foundation funds research for different types of stem cells, because each has specific advantages.
Retinal Tissue Derived from Stem Cells Targets Advanced Degeneration 
Photoreceptors, the cells that make vision possible, are not the only cells that can be affected by retinal disease.  Retinal pigment epithelial (RPE) cells, which provide essential waste removal and nutritional support for photoreceptors, are frequently lost, as well. David Gamm, M.D., Ph.D., at the University of Wisconsin-Madison, is pioneering the development of a stem-cell-derived retinal patch comprised of photoreceptor precursors and RPE cells. The patch includes a scaffold to provide structural support for the cells. The patch will also be wrapped in a biodegradable gel to hold the layers together. The photoreceptor precursors and RPE cells will be derived from iPSC, which are obtained from small skin or blood samples from human donors, whose immunological profiles are similar to those of the general population. That will reduce the risk of rejection of the transplanted therapy. Dr. Gamm and his colleagues are currently transplanting early versions of the patch in rodents. They have also begun identifying people for iPSC donations. Dr. Gamm’s collaborators include: Dennis Clegg, Ph.D., of the University of California, Santa Barbara, who is developing the scaffold; Cellular Dynamics International, under the guidance of Derek Hei, Ph.D., which is manufacturing the therapeutic cells; and Jamie Thomson, Ph.D., V.M.D., who discovered embryonic stem cells in 1997, and co-identified iPSC in 2007.
Pharmaceuticals and Small Molecules: Drugs taken as pills or eye drops have many potential advantages in treating retinal diseases. Often referred to as neuroprotective therapies, they may slow vision loss for a broad range of conditions, independent of the underlying genetic cause of disease. Also, dosing of the treatments can be easily increased or decreased, based on the needs of the patient.
Saving the Cell’s Power Supplies
MitoChem Therapeutics is developing a small molecule to boost mitochondrial function, and save vision, in people with a broad range of retinal diseases. Mitochondria are power supplies for all cells and play a key role in their survival. Bärbel Rohrer, Ph.D., and Craig Besson, Ph.D., the founders of MitoChem, have identified a molecule that performs well in preserving photoreceptors in different mouse models of retinal degeneration. Their goal now is to formulate the therapy as an eye drop that can reach the back of the human-sized eye. Once they have achieved that goal, they can begin studies in preparation for a clinical trial. The Foundation has invested more than $2 million in the MitoChem project.
Identifying Neuroprotective Molecules for Slowing Vision Loss
As a result of earlier vision-related research of a cancer drug, Don Zack, M.D., Ph.D., at Johns Hopkins University, believes that a certain group of naturally occurring proteins in the retina accelerates vision loss in people with retinal degenerations. His grant involves genetic engineering of mice to limit production of the proteins and determine if doing so leads to increased photoreceptor survival and vision preservation. Dr. Zack is also testing molecules that inhibit production of the proteins to identify those that are good candidates for safely and effectively preserving vision in humans with retinal diseases. He is collaborating with The Scripps Research Institute and the company BioMotiv to screen a 29,000-compound library of molecules. Matt LaVail, Ph.D., at the University of California, San Francisco, is conducting rodent studies in support of the project.
Screening Potential Vision-Saving Drugs in Zebrafish
Jeff Mumm, Ph.D., at Johns Hopkins University, is using robotics to screen a library of 3,300 drugs already approved by the U.S. Food and Drug Administration in a zebrafish model of retinal disease. His testing protocol will assess rod photoreceptor survival. Once he has identified potential therapeutic candidates, he will collaborate with Bärbel Rohrer, co-founder of MitoChem, to evaluate them in rodent models.