Jean Bennett studies the molecular genetics of inherited retinal degenerations with the idea of using this knowledge to develop rational approaches for treatment of these diseases. Target diseases include retinitis pigmentosa and age-related macular degeneration. Studies in her laboratory range from identifying the molecular bases of retinal degenerations, generating animal models for these diseases, evaluating novel vectors for retinal gene transfer, characterizing immune responses to gene transfer, developing novel gene-based approaches for reversal of sensory loss, and rescuing vision in animal models through gene based treatments. Dr. Bennett was one of the first investigators to use viral vectors to deliver transgenes to specific cells in the retina and also led the first team to demonstrate proof-of-principle of ocular gene therapy. She has developed a number of strategies for gene therapy-mediated treatments for retinal disease. Besides the eye, projects in Dr. Bennett's laboratory target other diseases/organs suffering from mutations in cilia proteins, including the ear (cochlea) and the kidney (renal tubular epithelium). Dr. Bennett's work leads naturally to translational research. For example, a study conducted in her lab and with collaborators at UPenn, Cornell and University of Florida led to a remarkable reversal of blindness in a canine model of a blinding disease affecting infants. This treatment is currently being tested in human clinical trials at several different Centers. Dr. Bennett is Scientific Director for the Phase I/II human clinical trial evaluating the safety and efficacy of gene transfer in Leber congenital amaurosis (LCA) due to RPE65 mutations. This trial is being carried out at The Children's Hospital of PHiladelphia (CHOP). This was the first study to report the exciting efficacy results in all twelve subjects, including 5 children.
"This mutant provides a model for retinitis pigmentosa 20 and Leber congenital amaurosis. There is slow retinal degeneration as assessed by histology, but rod ERG readings show profoundly diminished dark adapted responses by 1 month of age The light adapted ERG responses at 1 month are delayed and diminished amplitude occurs with age. At 3 months of age the fundus examination appears normal and at 5 months of age small, punctate, white spots appear beneath retinal vessels. At 15 months of age the fundus has a mildly pigmented granular and mottled appearance. Histology of the retina begins to show occasional voids in the outer segments of the photoreceptor cells at approximately 6 weeks of age and at 3 months of age the outer segments have more voids and are more disorganized but the outer segments and the outer nuclear layer remain predominantly intact and relatively normal. However, by 7 months the outer nuclear layer has 6 to 8 layers of outer nuclear layer remaining in the retina and the outer segments are noticeably shorter than normal, and at 27 months only 3 to 4 layers of the outer nuclear layer remain, the outer segments is significantly shorter than normal, and the retinal pigment epithelium is atrophied and hypopigmented. The retinal pigment epithelium shows small lipid-like droplets detectable by electron microscopy at 3 weeks of age and increasing in size and frequency at 3 months of age. Consistent with the disrupted function of RPE65 to convert all-trans retinal to 11-cis retinal, HPLC fails to detect 11-cis-retinal in the retinas of homozygotes, rhodopsin absorbance is not detectable from 2 weeks to 5 months of age, there is reduced opsin levels in retinas as early as 8 days of age, and a progressive increase in retinyl esters after 3 weeks of age."