Scientists Report Outstanding Progress in FFB-Funded Translational Research
December 7, 2011 - An international team of retinal scientists funded by the Foundation’s Translational Research Acceleration Program (TRAP) convened in Las Vegas on November 29 to report on their progress over the last year in moving promising treatments and cures out of the lab and into clinical trials. From the discovery of new vision-saving compounds, to success in preclinical studies of emerging gene and stem cell therapies, to the identification of new disease-causing genes, progress in these clinically focused research efforts is occurring at an unprecedented rate.
“The impact of the five-year, $100 million commitment from Gordon Gund and other key TRAP investors is phenomenal,” says Dr. Stephen Rose, chief research officer, Foundation Fighting Blindness. “TRAP is enabling the world’s top retinal researchers to immediately capitalize on the latest breakthroughs and innovations in science. What used to take us decades to accomplish is now taking us a year or two. The science is there, and TRAP is enabling us to more effectively and expeditiously move the knowledge and technology into human studies.”
TRAP was launched originally in 2008 as a $10 million per year program, but the program’s investors, recognizing the expansion of clinical opportunities for retinal treatments, doubled their funding commitment in early 2011.
Collaboration is Key to Success
While aggressive funding is essential to scientific progress, advances are not made in a vacuum. Collaboration has been critical to accelerating the clinically focused efforts of TRAP-funded researchers. For example, earlier this year, Dr. Ed Stone, director of the Carver Genetics Lab at the University of Iowa, found that defects in the MAK gene are a common cause of retinitis pigmentosa (RP) among people with Ashkenazi (Eastern European Jewish) descent. Using stem cell technologies being perfected by scientists like Dr. David Gamm at the University of Wisconsin–Madison, Dr. Stone and his colleague Dr. Budd Tucker were able to better evaluate how defects in the MAK gene cause vision loss and, at the same time, explore potential therapies for MAK-based RP. In turn, Dr. Gamm is using gene therapy technology developed in other labs to correct genetic defects in his emerging stem cell treatments — stem cells derived from skin or blood — so they can be used in a future retinal cell transplantation clinical trial.
“The cross pollination occurring among TRAP investigators is pervasive and invaluable. They can accomplish so much more, and at a faster pace, by sharing resources and knowledge. Everybody wins through open collaboration, especially the patients,” says Dr. Rose.
Gene Discoveries Open the Door to New Treatments, Clinical Trials
In 2011, both Dr. Stone and Dr. Stephen Daiger of the University of Texas Health Science Center at Houston used a highly efficient, state-of-the-art gene screening technology known as whole-exome sequencing to identify new genetic defects that cause retinal degenerative disease.
Dr. Stone’s work in finding MAK as a link to autosomal recessive RP (arRP) was recognized as a critical advancement, because it was found to be the cause of retinal disease in 20 of his previously undiagnosed patients and will undoubtedly be linked to arRP in dozens of other people around the United States and the world.
Dr. Daiger’s discovery of RPE65’s link to autosomal dominant RP (adRP) and the identification of other genetic regions linked to adRP and X-linked RP were important steps forward in diagnosing several affected families and providing targets for future treatments.
Through their genetic testing services, Drs. Stone and Daiger significantly expanded their collections of patient DNA and natural history information, which will not only provide new diagnoses for families, but also help identify candidates for forthcoming clinical trials.
Dr. Stone reports that his nonprofit genetic lab can now screen for 24 retinal degenerative diseases (50 genes), including: arRP, Leber congenital amaurosis (LCA), Stargardt disease and Usher syndrome. To date, the lab has found disease-causing genes in approximately 4,500 families from 50 states in the United States and 60 countries.
Advancements in Stem Cell Treatments on Multiple Fronts
Over the past year, Dr. Thomas Reh of the University of Washington continued his pioneering work in developing transplantation strategies for retinal disease treatments derived from embryonic stem cells (hESC). His goal was to produce viable retinal cells and successfully transplant them into various small and large animal models. This strategy provides potential for saving and restoring vision in people affected by a wide range of retinal conditions, including those with the most advanced vision loss.
Dr. Reh was successful in producing large quantities of viable retinal cells that survive when transplanted, and in some mouse models of retinal disease, they restored some visual function. His next step is to evaluate and perfect this strategy in larger animal models; doing so will position him well to gain FDA approval for a clinical trial.
As mentioned previously, Dr. David Gamm is using an innovative technique to derive stem cells from a patient’s skin or blood. Known as induced pluripotent stem cells (iPSC), they have many of the advantages of embryonic stem cells, namely flexibility and ease of replication. But the patient serves as his or her own cell donor; embryos are not needed. Over the past year, Dr. Gamm successfully derived stem cells from the skin of a patient with a retinal disease known as gyrate atrophy, and subsequently used gene therapy to correct the genetic defect in the cell. He was also successful in generating sheets of iPSC that might be used in a future transplantation clinical trial. His next step is to evaluate iPSC transplantation in animal models.
As was also mentioned, several researchers from around the world, such as Dr. Stone, are using iPSC as a method for studying retinal disease “in a dish” and testing the safety and efficacy of potential drugs and other treatment modalities.作者: 凤凰涅盘 时间: 2011-12-7 22:58
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Screening Drugs, Molecules and Plant Extracts to Find Vision-Saving Treatments
Using innovative screening technologies, four TRAP-funded investigators are each on a quest to find compounds that can preserve vision for people affected by a wide range of retinal diseases.
Dr. Bärbel Rohrer of the Medical University of South Carolina and her team previously screened 50,000 compounds to identify those that enhanced mitochondrial function. Mitochondria are the energy centers of all cells, including photoreceptors, and disease often compromises their function. Dr. Rohrer’s research indicates that compounds which enhance or preserve mitochondrial function will likely also halt vision loss.
After identifying two promising treatment candidates, Dr. Rohrer has been working to better understand what features of the compounds are making them protective, and producing enhanced, second generation versions of them for advancement into human studies.
Dr. Don Zack of the Wilmer Eye Institute at Johns Hopkins University previously screened a library of 5,000 FDA-approved drugs and compounds to identify those that save and protect retinal cells. He found that an anti-cancer drug, sunititib, as a promising neuroprotective candidate. He also discovered that a protein called stanniocalcin-1 (STC-1) has strong protective properties. He continues to perform studies of both of these agents to better understand their mechanisms of action and potential use in clinical trials.
Dr. Zack is also collaborating with Drs. Reh and Gamm as well as Dr. Michael Young of Schepens Eye Research Institute, Massachusetts Eye and Ear, to develop stem cell models of retinal disease for testing additional potential therapies.
Dr. Thierry Lêveillard of the Institut de la Vision, INSERM, in Paris previously screened 800 plant extracts to evaluate their potential for protecting cones, the photoreceptors that provide the vision most critical to our daily activities. The most promising extract proved to be Uvaria chamae, a large, fruit-bearing shrub in Africa. He is now working to identify the molecule(s) in the plant that are protective, with the goal of developing a treatment from them.
Dr. Matt LaVail of the University of California, San Francisco, is a recognized leader in the use of animal models to identify and study agents that may be neuroprotective for the degenerating retina. In addition to studying several of his own proteins and molecules, Dr. LaVail has collaborated with Drs. Rohrer and Zack to evaluate their treatment candidates in his rodent models. He also performed animal studies of valproic acid — an FDA-approved drug in FFB-funded clinical trials for adRP — to help determine which forms of RP would be most amenable to the treatment approach.
TRAP Makes Strong Commitment to Gene Therapies
Leveraging the success of the first-ever clinical trials of gene therapy for retinal degenerative disease — studies that have restored some vision in 40 children and young adults who were virtually blind from LCA — the Foundation recently announced TRAP-based support of $8.25 million for six, three-year gene therapy grants. To be eligible for the funding, each of the recipients was required to submit a plan indicating how they would be ready to seek authorization from the FDA to launch a clinical trial within three years. The projects include gene therapies for: two forms of LCA (RPGRIP1 and GUCY2D), choroideremia, adRP, X-linked retinoschisis (XLRS), a nanoparticle gene delivery system for delivering larger genes, and an optogenetic therapy to harness and revive a variety of retinal cell types for vision.
Dr. Jeff Chulay, chief medical officer of Applied Genetic Technologies Corporation, discussed his FFB-funded collaboration with Oregon Health & Sciences University in developing a gene therapy for XLRS. He noted that the treatment has the opportunity to benefit as many as 35,000 affected people in the United States and Europe. He said that without TRAP funding, the final preclinical steps in development of the gene therapy, including optimization of the viral delivery system and a final large animal study, would not be possible.
Earlier this year, Dr. John Flannery of the University of California, Berkeley, successfully used gene therapy to empower ganglion cells of the retina to respond to light in a mouse model of retinal degeneration in which all photoreceptors had been lost. While not a TRAP-funded investigator, he provided an overview of his work, the growing and promising field of optogenetics, and a TRAP-funded cone-restoration effort being conducted at the Institut de la Vision in Paris.
Dr. William Hauswirth of the University of Florida, a world leader in gene delivery technology development and a TRAP-funded investigator working on a gene therapy for adRP, discussed the current status of gene therapy research for retinal degenerative diseases. He noted that gene therapies have been successful in at least 17 preclinical disease models, and that clinical trials for six different diseases — LCA, arRP, choroideremia, Usher syndrome, Stargardt disease and wet age-related macular degeneration — are underway. (The Usher syndrome trial is scheduled to begin before the end of 2011.)
TRAP Supports Clinical Advancement of Valproic Acid for RP
Earlier in 2011, FFB launched a three-year, 90-participant human study of valproic acid, a drug already FDA-approved for seizure disorders, in its National Eye Evaluation Research network. Dr. Rose discussed how TRAP funding was essential in determining which patients should be enrolled in the trial. Previous lab studies and clinical observations had shown that valproic acid was an excellent candidate for slowing vision loss in people with adRP. However, there was little data showing the drug’s effect on people with arRP. In subsequent TRAP-funded lab studies, scientists determined that valproic acid did not preserve vision in arRP. As a result of these findings, only people with adRP are being enrolled.
Dr. Rose also noted that the valproic acid trial is being expanded from two sites — the University of Utah and Retina Foundation of the Southwest — to as many as five sites in an effort to increase patient enrollment.
TRAP-Funded Clinician-Scientist to Provide Critical Clinical Trial Support
One of the biggest challenges for researchers conducting clinical trials for retinal degenerative disease treatments is developing and selecting outcome measures that can indicate whether or not the therapy is working. In many retinal conditions, traditional study endpoints, such as visual acuity and visual field, will not give a complete picture of the treatment’s efficacy.
Dr. Hendrik Scholl of the Wilmer Eye Institute at Johns Hopkins University — an up-and-coming clinician-scientist and recipient of a TRAP career development award — is developing high-resolution imaging and functional mapping techniques to more effectively evaluate the efficacy of potential therapies. In addition to publishing several peer-reviewed research papers on his innovations, Dr. Scholl will be using these imaging and mapping tools in early-stage clinical trials of treatments for LCA, RP and Stargardt disease.
Staying Tuned
For more information on advancements and breakthroughs being made by TRAP-funded researchers, register online at www.FightBlindness.org to receive the Foundation’s newsletters and news announcements.
Also, several TRAP investigators will be presenting at the 2012 VISIONS Conference, being held June 28-July 1 in Minneapolis. Registration for the event is now open.作者: 凤凰涅盘 时间: 2011-12-7 23:01
November, 28, 2011 - Foundation-funded researchers from the University of Florida have taken a major step forward in the development of a vision-restoring, gene-replacement therapy for people with Leber congenital amaurosis (LCA) caused by mutations in the gene GUCY2D. They demonstrated that efficacy of the treatment in a mouse model of the condition was sustained for a year, a significant improvement over earlier studies in which the treatment’s effect lasted three months. The investigators believe that given these latest results, a similar treatment could last for several years or possibly a lifetime in humans.
