Optimising the benefits of retinal gene therapy using animal models of Leber’s Congenital Amaurosis

Project Aim

The aim of the project was to assess the long-term effects of gene therapy in dogs with a specific mutation causing Leber’s Congenital Amaurosis (LCA). LCA is a rare and severe form of Retinitis Pigmentosa that results in vision loss from an early age. The project focused on evaluating the therapeutic effects of gene transfer and studying the correlation between functional improvements and changes in retinal structure over a period of 4 years.

Project Results and Impact

The gene therapy surgeries performed on the affected dogs were successful, and functional vision was regained within 4-6 weeks after the procedure. Long-term follow-up using simultaneous bilateral electroretinography (ERG) demonstrated sustained improvement in retinal function throughout the 4-year period. However, there was a decline in rod function that correlated with a decrease in the number of photoreceptor cells in the treated retina. In the specific area where the gene therapy was administered, the photoreceptor cells showed well-preserved morphology and exhibited normal activities like disc shedding. However, outside of this treated region, the retinal degeneration continued to progress.

The findings suggest that the functional recovery after subretinal gene therapy is limited to a small region, smaller than the actual injection area. Despite this, the improved area was sufficient to elicit approximately 50% of the normal ERG responses and provide long-term functional vision. The success of gene transfer studies in different strains of LCA indicates the feasibility of retinal gene therapy and the potential for long-term improvement in visual function.

Future studies should focus on developing more effective and less invasive treatment approaches for gene therapy. The research conducted in this project has paved the way for further advancements in the field of retinal gene therapy and offers hope for individuals with LCA and other retinal degenerative diseases. The results have been published in a scientific paper, contributing to the knowledge and understanding of retinal gene therapy.

Published peer reviewed article

Narfstrom K, Seeliger MW, Lai CM, Vaegan, Katz ML, Rakoczy EP, Reme C. Morphological aspects on the long-term functional improvement of the retina 4 years following rAAV-mediated gene transfer in the RPE65 null mutation dog. Adv Exp Med Biol. 2008. 613:139-46.

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