Shiming Chen, PhD

Washington University - Visionary

Project Title: rAAV Gene Therapy in Mouse Models of CRX-Associated Retinal Degenerative Diseases

 

The goal of this proposal is to develop safe, effective therapies for retinal degenerative diseases resulting from mutations in the transcription factor CRX. Human CRX mutations are linked to blinding diseases: retinitis pigmentosa, cone-rod dystrophy and Leber’s congenital amaurosis. To date, little has been done to develop therapies for diseases caused by genetic defects in retinal transcription factors. These factors coordinate the expression of sets of genes that work together to carry out a cell’s functions, like converting light to a neural signal in photoreceptors (rods and cones). Mutations in transcription factors have a wide-spread effect because these factors interact with each other and other proteins in a synergistic manner. Changing the function of one transcription factor affects a much larger group of proteins, creating potentially devastating effects on gene expression. The complexity of these changes makes designing drug-based approaches exceedingly difficult. We anticipate that the best therapy strategy is to supply a corrected copy of the CRX gene to the affected cells. For this reason we have chosen gene therapy as the best approach. Gene therapy uses a modified non-replicating virus to deliver intact copies of genes to cells with genetic defects. Often delivering a single gene is sufficient to completely restore the function of the cell. In animal models of retinal diseases, treatment strategies using the recombinant adeno-associated virus (rAAV) vector have both improved the vision of visually impaired animals and restored vision to previously blind animals.

 

Human clinical trials have also shown that rAAV gene therapy is both safe and effective, establishing rAAVmediated gene therapy as a promising treatment for retinal degenerative diseases. Therapy development for transcription factor-related retinal diseases has been delayed because of the lack of good animal models to test potential treatments and the unique obstacles caused by transcription factors’ complex interactions. CRX exerts the most central function of the disease-causing retinal transcription factors, as it is required for the expression of many genes in both rods and cones. We have developed two new mutant mouse models (R90W and E168d2) that replicate CRX-associated human disease much more closely than the previous Crx knock-out (Crx-/-) model. For the first time, these models will permit the evaluation of gene therapy in treating this important class of blinding diseases.