All seven awardees contributed to development of gene therapy for the blinding disorder Leber congenital amaurosis
September 4, 2018
NEI
Photo shows T. Michael Redmond, Ph.D.

T. Michael Redmond, Ph.D

Vision researcher, T. Michael Redmond, Ph.D., chief of the National Eye Institute (NEI) Laboratory of Retinal Cell and Molecular Biology, is a recipient of the 2018 António Champalimaud Vision Award for foundational science discoveries about the molecular biology of the retina, the light-sensing tissue at the back of the eye. His work deduced how the RPE65 gene converts dietary vitamin A into a form of the vitamin that is central to the workings of the visual cycle, the enzymatic processes by which the eye converts light into electrical signals sent to the brain.

The award will be shared by seven scientists, including Redmond. These researchers, four of whom were supported by NEI, are being recognized for contributions that led to the development of the gene therapy Luxturna (voretigene neparvovec-rzyl) for treating Leber congenital amaurosis (LCA). LCA is an inherited genetic disorder in which children with severe RPE65 mutations can be born blind. Those with less severe mutations may have some vision at birth, but often become blind by young adulthood.

“We owe much to Michael Redmond for establishing that defects in the retinal pigment epithelium are among the causes of diseases such as LCA and retinitis pigmentosa, and for setting a course toward an effective gene therapy approach to treat them,” said NEI Director Paul A. Sieving, M.D., Ph.D.

In the 1990s Redmond cloned the RPE65 gene along with NEI research fellow, the late Christian Hamel, M.D., Ph.D., who later moved to the Institute for Neurosciences of Montpellier, France. At the time, they could only speculate as to its function. “We knew it was expressed solely in the retinal pigment epithelial (RPE) cells,” said Redmond. The RPE is a single layer of cells located between the retina and the choroidal blood supply that plays a key role in keeping light-sensing photoreceptors healthy.

“We also knew that RPE65 shared characteristics with enzymes in bacteria and plants that metabolized carotenoids, some of which are precursors of vitamin A,” Redmond said.

Redmond and Hamel postulated that people born with RPE65 mutations would likely have the most severe retinal degeneration and blindness at birth. By 1997, their sequencing of the RPE65 gene in individuals with LCA confirmed their hunch by allowing them to identify individuals who were indeed blind due to “loss of function” mutations in their RPE65 genes, now recognized as a cause of LCA.

To characterize the gene’s function, Redmond and colleagues developed an RPE65 knockout mouse model. Mice without the RPE65 gene were completely blind and insensitive to light, which they found was associated with an inability of their retinas to metabolize vitamin A into 11-cis retinal, a photosensitive derivative of vitamin A and the form required for the visual pigment rhodopsin to absorb light. After further study, they confirmed that RPE65 is the enzyme responsible for converting dietary vitamin A into 11-cis retinal, a key step in the ability of the retina’s photoreceptors to detect light and convert it into an electrical signal.

The RPE knockout mouse model also provided the first animal model of LCA, which laid the groundwork for developing and testing a gene therapy to treat it. Later, dogs were found to have a naturally occurring form of RPE65 retinopathy that served as a more biologically relevant model to further test and advance the development of gene therapy. Dogs born blind due to the RPE65 mutation were successfully treated with gene therapy in 2001.

By 2008, clinical trials funded by the NEI and others showed benefits from gene therapy administered to young adults with LCA. Within weeks of treatment, most patients reported having brighter and clearer vision, and retinal studies showed improvements in sensitivity to light. The U.S. Food and Drug Administration approved Luxturna in 2017 for the treatment of patients with RPE65 mutation-associated retinal dystrophy, a group of disorders that include LCA. Luxturna is the first FDA-approved gene-replacement therapy of any kind to be approved.

In addition to Redmond, other NEI-supported researchers awarded the prize include Jean Bennett, M.D., Ph.D., and Albert M. Maguire, M.D., University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia; Samuel Jacobson, M.D., Ph.D., Scheie Eye Institute, University of Pennsylvania School of Medicine, and William W. Hauswirth, Ph.D., University of Florida College of Medicine, Gainsville. Robin Ali, Ph.D., and James Bainbridge, M.D., Ph.D., Institute of Ophthalmology of the University College London and Moorsfields Eye Hospital, also were recognized.

The António Champalimaud Vision Award was launched in 2006 and is considered among the most prestigious vision science prizes. In even-numbered years, it is bestowed to basic and clinical scientific researchers, and in odd-numbered years, institutions are recognized for their on-the-ground efforts to prevent and cure blindness and vision disorders, primarily in developing countries. The Champalimaud Foundation, based in Lisbon, Portugal, was established by the late entrepreneur António de Sommer Champalimaud.

Redmond’s award will be given to the NEI in support of his research. For more information about his lab, visit https://irp.nih.gov/pi/t-michael-redmond

Contact

Kathryn DeMott
301-496-5248