Grant: Project Grant

Zellweger Spectrum Disorder (ZSD) is commonly caused by mutations in the PEX1 gene, resulting in reduced functions of peroxisomes, organelles found in all body cells. Progressive retinal degeneration leading to blindness is a major untreatable disability, and there is urgency amongst patients and families to provide a therapy that preserves vision for improved communication, learning, mobility, autonomy and employment opportunities. To address this, our group developed PEX1 gene therapy for the retina using our PEX1-deficient mouse model and achieved remarkable structural and functional improvements in the retina of treated animals. We are now poised to move this therapy towards clinical translation, using the necessary steps outlined in this proposal. Our main aims are to: (i) Complete biodistribution studies in mice over 1 year. This will be done by measuring human PEX1 mRNA levels in tissues inside and outside the eye, using our optimal dose of gene therapy vector and several time frames, and (ii) Identify the best patient candidates and outcome measures of vision improvement to use in a clinical trial. This will be done by performing a wide array of ophthalmological and functional vision tests on 30 patients yearly for 5 years. We anticipate that interim data at 2 years will allow for clinical trial planning. In addition, the results of these vision studies, never done systematically in ZSD patients, will inform the stages through which peroxisome dysfunction leads to retinal degeneration. Completing these compulsory aims is required by regulatory agencies (Health Canada, FDA, EMA) to initiate the clinical trial application process. In parallel, we will continue our business development efforts to secure a successful industry partnership for human clinical trials. The information gained from our proposed research will enable this, by providing the foundational data bridging the gap between proof-of-concept and commercialization.