Grant: Op. Grant :Bringing Rare Disease Gene Therapies to Clinical Trial Readiness- LOI

Rare brain disorders can affect children at birth or develop later on in life. They can affect all levels of brain functioning and drastically impair daily functioning. A mutation in a single gene is known to cause many rare brain disorders and thus some can be candidates for gene therapy. Gene therapy is the targeting of the underlying genetic cause of disease to decrease or stop symptoms. We are a team of basic and clinician scientists at the Montreal Neurological Institute and the Montreal Children's Hospital. We are currently running clinical trials in gene therapy at our hospitals. The purpose of this application is to build the evidence for a phase 1 clinical trial for 5 rare brain disorders that cover a spectrum of severity, age of onset, and disease mechanism. In starting with five disorders in which we have extensive experience we hope to establish the framework of gene therapy development to other rare brain disorders. This grant will look at diseases LNS, SGS, ARSACS, OPMD, and FRDA, and we have candidate gene therapies for three of these five ready to test. We have also made human and animal models of disease in which to test and optimize gene therapies. Using these five disorders as flagships which are at different points of clinical trial readiness, we want to achieve 6 main objectives in this project: 1) To test and select an appropriate Adeno-Associated Virus for use in brain, by assessing biodistribution in marmoset; 2) To finalize the establishment of human cell lines for all diseases from multiple patients; 3) To make and optimize the genetic payload for LNS and FRDA, two disease where we have not yet designed a gene therapy; 4) To test efficacy and safety of gene therapies in human and mouse models of disease; 5) To identify outcome measures suitable to use in gene therapy clinical trials to assess efficacy in patients; 6) To ensure a strong plan for equitable access and knowledge mobilization of this work.