Grant: Project Grant

Zellweger Spectrum Disorder (ZSD) is commonly caused by mutations in the PEX1 gene, resulting in peroxisome dysfunction. Visual impairment is a major untreatable handicap for ZSD patients, and alleviating this burden would enable improved communication, learning, mobility, autonomy and employment opportunities. To address this, our group recently tested the effects of PEX1 gene therapy in the retina of our PEX1-deficient mouse model for ZSD, and found significantly improved retinal function and peroxisome metabolites in the retina of treated animals. The proposed research is needed to complete the preclinical development of retinal gene therapy for ZSD. Our main aims are to (i) establish the optimal gene therapy delivery design and dose to use in the transition towards the clinic, (ii) expand outcome measures for testing of PEX1 retinal gene therapy in mice, which will allow for additional functional testing and dose-response correlation, and (iii) perform an expanded efficacy trial in our mouse model. Completing these necessary aims will allow us to move directly into meetings with Health Canada and the FDA to forge a path to the clinic. In addition, the results of these studies, never before done in peroxisome deficient animal models, will inform the mechanism by which peroxisome dysfunction leads to retinal degeneration. Finally, the development of this cutting-edge therapy for ZSD will support the use of gene replacement therapies to treat other genetic diseases.