Blindness is often caused by genetic lesions that directly affect photoreceptors. There are >200 disease genes in humans that lead to blindness ( Addressing each genetic deficit by transduction of a gene specific to that disease would be a large and expensive undertaking. As an alternative, gene therapy can be used to attack a problem common to multiple genetic forms of blindness. One such approach is to preserve cone function in retinitis pigmentosa (RP). People with RP initially have poor night vision, as rods are dysfunctional. Rods are then lost, which is followed by loss of cone function, and then cones themselves. As cones do not express the disease gene in most cases, there must be a non-autonomous cause of cone death. If this cause can be identified, and combated, a more generic form of therapy can be developed. Using 4 mouse models of RP, and an unbiased microarray approach, we discovered that many genes involved in the regulation of metabolism were altered at the onset of cone death. We further showed that mTOR, a key regulator of metabolism, was not phosphorylated in RP cones. This is now the earliest sign of cone stress in RP that is known. As the disease progressed, we discovered that cones carried out chaperone- mediated autophagy. Injection of insulin into RP mice, which can lead to increased activity of mTOR, increased survival of cones. We have suggested a model wherein cones are dysfunctional and then die due to dysregulated metabolism. As rods are the major cell type in the ONL, cones experience a greatly altered environment following rod death. The cone OS collapse, they lose their intimate association with the RPE, and they are exposed to a hyperoxic environment. They show greater oxidation of their nucleic acids, proteins, and lipids. Fighting oxidation may cause cones to require more NADPH, which is generated from glucose via the pentose phosphate pathway (PPP). It is also produced by two cytosolic enzymes, malic enzyme and isocitrate dehydrogenase. If glucose is shuttled to the PPP, the glycolytic pathway would slow, which could lead to several metabolic outcomes, including reducing the surface area of cones, as well as reducing phototransduction and potentially the ATP levels. We wish to develop AAV-mediated gene therapy to combat metabolic stress in the cones in RP. As cone-mediated vision is of greatest importance to humans, preservation of cone function is critical to the quality of life among RP patients. If such therapies can be developed, it is also possible that these therapies can be extended to other diseases where cones are compromised, such as age-related macular degeneration (AMD).

Public Health Relevance

There are >200 disease genes known that cause the onset of blindness among humans. While gene therapy using AAV vectors has proven to be safe and effective for the eye in humans, it will too expensive to mount a clinical trial for a viral vector directed specifically towards each genetic cause of blindness. We propose to develop AAV-mediated gene therapy to prolong the function and survival of cone photoreceptors in retinitis pigmentosa, as a general strategy to sustain color and daylight vision.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (DPVS)
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Shen, Grace L
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Harvard University
Schools of Medicine
United States
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