Scientists Report Significant Advancements in Clinically Focused Retinal Research

December 13, 2012

A group of the world’s leading retinal researchers met in Las Vegas November 25-27 to report on their progress in advancing potential vision-saving therapies for retinal diseases into human studies. Several of the investigators — including those developing cross-cutting gene therapies, stem cell treatments derived from skin and vision-preserving plant extracts — are within three to five years from moving their research into clinical trials. Some researchers presented plans for launching clinical trials as early as 2014 or 2015.

Funded through the Foundation’s Translational Research Acceleration Program (TRAP), the team is receiving $20 million annually for clinical development of its emerging therapies.

TRAP also supports projects for genetic testing, the discovery of new disease-causing genes and imaging studies to better understand retinal disease processes and treatment effectiveness.

“Translational science — moving a potential treatment out of the lab and into a clinical trial — is exceptionally challenging because of the increased cost and risk associated with human research. TRAP is the Foundation’s full-court press for addressing the translational challenge,” says Dr. Stephen Rose, the Foundation’s chief research officer. “Our annual TRAP meeting provides an invaluable opportunity for the research teams to not only discuss their progress, but also continue their collaborations, build new working relationships and refine their strategies for moving forward. It’s a remarkably productive gathering of some of the world’s top retinal experts.”

TRAP was established by Gordon Gund, co-founder and chairman of the Foundation, along with other key research investors. “Now is the time for the Foundation to capitalize on the breakthroughs being made in retinal research labs around the world,” says Gund. “It is incumbent upon us to drive the translational work to leverage the science into human studies, so we can develop treatments and cures and get them out to the people who need them.”

Thanks to the advances being made in several projects, TRAP-funded researchers are attracting critical investments from the commercial sector. “Because these translational efforts require substantial financial investments, it is imperative that we partner with pharmaceutical companies and industry to bolster our drive to the clinic. We can’t always do it alone,” explains Dr. Rose. “Our TRAP investigators are doing an outstanding job demonstrating that their treatments have strong market potential, and most important, the potential to save and restore vision.”

Annual highlights of the progress being made in the 15 TRAP-funded research projects are provided below:

Drug Discovery

Compounds Protect Retinal Cells, Show Strong Cross-Cutting Potential

After screening an initial library of 50,000 compounds, Drs. Bärbel Rohrer and Craig Beeson of the Medical University of South Carolina have identified two demonstrating strong potential for saving vision for people affected by a broad range of retinal diseases. Those conditions include: retinitis pigmentosa (RP), cone-rod dystrophy, Bardet-Biedl syndrome, Usher syndrome, Stargardt disease and age-related macular degeneration. The compounds work by protecting mitochondria, which are the power supplies for all the cells in the body including those in the retina.

The investigators have refined the compounds to the point where they save virtually all of the photoreceptors in a mouse model of retinal degeneration. They have also shown that eye drops can effectively deliver large amounts of one compound to the retinas in human-sized eyes. Eye drops are often the most practical delivery approach, because they minimize potential systemic side effects.

In preparation for gaining FDA authorization to launch a clinical trial, the researchers are selecting a lead compound, which will be further evaluated in safety and efficacy studies.

TRAP funding has enabled the team to establish a biotechnology company called MitoChem Therapeutics to facilitate its drug-development efforts.

FDA-Approved Anti-Cancer Drug May Preserve Vision

Dr. Donald Zack, of the Wilmer Eye Institute at Johns Hopkins University, has identified sunitinib, an FDA-approved anti-cancer drug, as being a potent protector of photoreceptors in a rodent model of retinitis pigmentosa. Because sunitinib is FDA approved, clinical development of it for retinal diseases should be quicker than it would if it were not yet approved.

In collaboration with Dr. Matthew LaVail, a TRAP-funded investigator from the University of California, San Francisco, Dr. Zack is continuing to evaluate sunitinib and similar compounds for their safety and vision-protecting effects. The researchers believe that these compounds may preserve vision for people affected by a wide range of retinal diseases.

Dr. Zack is also communicating with the pharmaceutical company which makes sunitinib about a possible retinal drug-development partnership.

Plant Extract Shows Promise for Protecting Cones

Cones are the photoreceptors most critical to everyday activities; they provide central and daytime vision, as well as the ability to perceive details and colors. Dr. Thierry Léveillard of the Institut de la Vision in Paris, France, has identified a plant extract which shows strong potential for protecting cones in retinas affected by degenerative diseases.

He is now searching for the specific molecules, or combination of molecules, from the extract, which will have the strongest protective effect. Once the optimal molecule(s) are found, he will evaluate their safety and effectiveness in animal models of retinitis pigmentosa with the goal of launching a clinical trial.

Stem Cell Treatments

Deriving Stem Cell Treatments from Patients’ Skin and Blood

Dr. David Gamm of the University of Wisconsin-Madison is a leading innovator in the process of deriving stem cells from the blood or skin of affected patients. Known as induced pluripotent stem cells or iPSC, these cells can be coaxed into becoming retinal cells for use as a customized treatment. Researchers are also using iPSC for increasing their understanding of retinal disease causes and identifying potential vision-preserving treatments such as drugs and gene therapies.

Dr. Gamm has made significant progress in coaxing the iPSC to become the retinal cell types needed for transplantation (e.g., rods, cones, and retinal pigment epithelium) and correcting the underlying genetic defect so the transplanted cells are free of retinal disease. Through the use of biological scaffolding, he has made advancements in getting the transplanted cells to functionally integrate into the recipient’s retina, though integration remains the greatest challenge.

Dr. Gamm notes that, through his colleagues at the University of Wisconsin-Madison, he has access to resources for making cell lines for use in future human studies.

In addition, he has used iPSC to create human models of Best disease and gyrate atrophy, which have led to a better understanding of why the conditions cause vision loss. He plans to use these models to also evaluate potential treatments.

Transplanting Stem Cells to Restore Vision

Dr. Thomas Reh, of the University of Washington, is making excellent progress in the development of a vision-restoring treatment derived from human embryonic stem cells (hESC). The future therapy will replace photoreceptors lost to a broad range of retinal diseases including retinitis pigmentosa.

He has thus far made significant progress in: developing retina-directed cells from hESC; transplanting the cells in large and small animal models safely and without immunosuppression; and facilitating cell integration into the recipients’ retinas. He notes that additional large animal studies — to improve cell survival and integration — will be necessary before he can seek FDA authorization for a clinical trial.

Gene Therapy

Retinoschisis Gene Therapy Advances Toward Clinical Trial

Applied Genetic Technologies Corporation (AGTC), in collaboration with Oregon Health & Science University and the University of Florida, is developing a gene therapy for X-linked retinoschisis, an inherited disease in males which causes vision loss from splitting of the layers of the retina. Dr. Jeff Chulay, the study’s principal investigator, said that the company plans to seek FDA authorization to launch a clinical trial for the treatment in late 2014.

Dr. Chulay’s team has made significant progress in identifying the best vector — the adeno-associated virus (AAV) that delivers copies of the therapeutic to the retina — for use in the forthcoming clinical trial. In preparation for the trial, the team will complete additional toxicology and biodistribution studies, identify study participants and obtain clinical-grade treatment vector.

Thanks to the Foundation’s TRAP funding and success in its gene therapy program, AGTC has received $37.5 million in venture capital funding for clinical development of treatments for XLRS and achromatopsia, a retinal disease that causes cone dysfunction, which leads to day blindness.

Clinical Trial of LCA1 Gene Therapy Planned for Late 2014

Caused by mutations in the gene GUCY2D, Leber congenital amaurosis type 1 (LCA1) is a retinal disease causing severe vision loss in children. Dr. William Hauswirth, of the University of Florida, has developed an AAV-based gene therapy that has worked successfully in mice with LCA1, positioning the treatment well for a clinical trial. Additional toxicology and biodistribution studies are planned in preparation for the trial. The University of Florida will produce clinical-grade AAV for the study.

Dr. Samuel Jacobson, of the University of Pennsylvania, has identified 11 patients — ages 6 months to 37 years — for potential participation in the clinical trial.

Restoring Vision by Reactivating Cones

In retinal diseases such as retinitis pigmentosa, cone cells — the cells that provide central vision and the ability to perceive color and detail — go into a dormant state; they are still alive, but they no longer provide vision.

A team led by Dr. José Sahel, of the Institut de la Vision in Paris, France, is developing a gene therapy that reactivates cones for restoring vision. The treatment works by delivering copies of a gene called halorhodopsin to the affected cones. The gene leads to production of a protein which makes the cones light-sensitive. The investigators plan to launch a clinical trial of the treatment in 2015.

Dr. Deniz Dalkara, a member of the team, reported that halorhodopsin has successfully restored vision in mice. The Sahel laboratory’s initial, large-animal studies of the AAV gene-delivery system for getting halorhodopsin to cones have also been successful. In addition, they have shown that halorhodopsin can modulate activity in human cones.

Additional animal studies to demonstrate long-term safety and effectiveness will be performed prior to clinical toxicology and biodistribution studies and clinical-grade therapy manufacturing. The team plans to launch a clinical trial of the treatment in 2015.

Advancing Gene Therapy for Choroideremia into a Clinical Trial

Dr. Jean Bennett, the pioneer who led the development of a vision-restoring gene therapy for children and young adults affected with Leber congenital amaurosis type 2 (RPE65 mutations), has made excellent progress in the development of a gene therapy for people with choroideremia. This retinal disease not only affects the choroid, a vascular layer of tissue covering the outside of the retina, but photoreceptors and retinal pigment epithelial cells as well. Dr. Bennett plans to launch a clinical trial of the treatment in late 2013.

Working in labs at both the University of Pennsylvania and The Children’s Hospital of Philadelphia, she has demonstrated efficacy of her AAV-based gene therapy in a choroideremia mouse model and human retinal cells derived from induced pluripotent stem cells. Over the next year, Dr. Bennett plans to: conduct a final safety study, recruit participants for the clinical trial, develop clinical-grade treatment vector, and gain regulatory authorization to launch the human study.

Clinical Development of Gene Therapy for LCA6

Dr. Eliot Berson, of the Massachusetts Eye and Ear Infirmary, is developing an AAV-based gene therapy for Leber congenital amaurosis 6, which is caused by mutations in the gene RPGRIP1. Dr. Basil Pawlyk, a member of Dr. Berson’s team, reported that the lab successfully completed a pilot mouse study of the treatment, and is now conducting a six-month, three-dose study in mice to further validate safety and efficacy. The researchers will begin clinical preparations — including toxicology studies and development of clinical-grade AAV — if the second mouse study yields favorable results. They hope to launch a clinical trial of the treatment in 2014.

Nanoparticles for Delivering Large Genes

While gene-delivery systems based on human-engineered viruses have performed well thus far in clinical trials, there is a limit to the size of the gene they can deliver. Replacement genes for some retinal diseases won’t fit in these viruses. To address this issue, Dr. Muna Naash, of Oklahoma University, is developing a nanoparticle gene delivery system, which can accommodate a gene of virtually any size.

Nanoparticles are tiny manmade particles, 1/12,000 the diameter of a human hair. Scientists are able to wrap corrective DNA in nanoparticles, and because they are so small, they can readily penetrate retinal cells to deliver their therapeutic genetic cargo.

Dr. Muna Naash is developing nanoparticle therapies for Stargardt disease, Usher syndrome type 2A, and a form of autosomal dominant retinitis pigmentosa (adRP) caused by mutations in the RDS gene.


Genetic Screening and Discovery for Autosomal Recessive Retinal Disease

Finding and characterizing the genetic defects that lead to retinal disease is a critical step in patient diagnosis and therapy development. Dr. Ed Stone, director of the Carver Genetics Lab at the University of Iowa, has identified disease-causing genetic mutations in more than 5,000 patients from every corner of the globe. Also, using a combination of innovative genetic sequencing tools, including next-generation sequencing, he is discovering new genes linked to retinal degenerations.

Carver Lab now offers nonprofit genetic tests for 24 inherited eye diseases (60 genes), including autosomal recessive RP (arRP) and X-linked RP.

Over the past year, TRAP funding has enabled the Carver Lab to collect and screen DNA from an additional 205 individuals with Stargardt disease, arRP, Usher syndrome and Bardet-Biedl syndrome.

Dr. Stone notes that if the disease-causing mutation for a particular individual or family can’t be found, they are enrolled in his laboratory’s gene discovery projects.

As in the case of the MAK gene discovery made in 2011, Dr. Stone is working with other labs at the University of Iowa to better understand newly discovered disease-causing genes and develop potential therapies. For example, his colleague Dr. Budd Tucker was able to create induced pluripotent stem cells (iPSC) from a patient with RP caused by a MAK mutation. Dr. Tucker developed the iPSC into retinal cells to understand why vision loss occurred and created a gene therapy that could potentially correct the cells’ RP-causing defect.

Genetic Screening and Discovery for Autosomal Dominant Retinitis Pigmentosa

Dr. Stephen Daiger, of the University of Texas Health Sciences Center in Houston, runs one of the world’s foremost labs for genetic testing and gene discovery for people with autosomal dominant retinitis pigmentosa.

Of 262 newly enrolled families, Dr. Daiger’s lab was able to find the disease-causing defect in about 50 percent. He subsequently used a series of next-generation sequencing techniques to find an additional 22 percent of the genetic defects in 80 of the remaining families.

Dr. Daiger’s lab now has a total of 1,700 families registered in its database. Thanks to advances in technology and the growing number of known retinal disease genes, the lab can find the disease-causing genetic defect in approximately 70 percent of the families with adRP.

Successful genetic testing enables patients to confirm their diagnosis and determine which forthcoming treatments and clinical trials may be appropriate for them. In addition, the discovery of new disease-causing genes gives treatment targets to retinal researchers from around the world.

Advances in Clinical Research

Valproic Acid Clinical Trial Expands

To increase participant enrollment, the Foundation increased the number of sites from two to six for its clinical trial of valproic acid, an FDA-approved anti-seizure drug that shows potential for slowing vision loss in people with autosomal dominant retinitis pigmentosa (adRP).

The current study sites are: the University of Utah, the Retina Foundation of the Southwest, the University of Tennessee, the University of Miami, Oregon Health &Science University and the University of Michigan.

Dr. Patricia Zilliox, chief drug development officer with the Foundation’s Clinical Research Institute (CRI), reported that a total of 35 people are now enrolled in the study. Her goal is to have 90 patients enrolled by April 2013.

Earlier lab studies and limited clinical evaluations suggested that valproic acid preserved vision in adRP.

Because valproic acid is already FDA-approved, clinical development of the drug for adRP should be quicker and less costly than if it were not yet approved.

Dr. Zilliox notes that people should not take valproic acid outside of the CRI study, unless under the supervision of a knowledgeable physician, because of the drug’s potentially serious side effects.

Advancing Clinical Expertise and Imaging Technologies for Retinal Degenerations

Thanks in part to a TRAP career development award, Dr. Hendrik Scholl, of the Wilmer Eye Institute at Johns Hopkins University, is quickly becoming a top clinical researcher for retinal degenerative diseases. He joined Wilmer in 2010 and is currently the head of the Institute’s Visual Neurophysiology Service.

Dr. Scholl is an expert in using state-of-the art imaging technologies to measure retinal structure and function in affected patients. His knowledge is valuable in measuring disease progress as well as the effect of emerging treatments in human studies.

He is leading a natural history study for people with Stargardt disease. Known as ProgStar, the investigation is helping determine the optimal outcome measures for emerging Stargardt disease treatments clinical trials.

Dr. Scholl is also an investigator in a clinical trial for a drug developed by QLT, which has improved vision for people with certain forms of retinitis pigmentosa and Leber congenital amaurosis.