Grant: Project Grant

Friedreich Ataxia (FRDA) is the most common form of hereditary ataxia. This is a recessive disease, i.e., both parents have to be carriers of the mutated gene. However, they are not symptomatic. Only the child who inherits two copies of the mutated gene will develop the disease. It is important to note that in the province of Quebec because of the low number of initial colons from France, ONE QUEBECKER OUT OF 50 IS A CARRIER OF THAT DISEASE! It is thus important to pursue in Canada research on the development of a therapy for this disease. The mutation responsible for Friedreich is an unusual expansion of the GAA trinucleotide in the frataxin gene leading to a reduced expression of frataxin resulting in cell death. Neuron death leads to coordination problems (confining patient to wheel chair) and cardiomyocytes death to cardiac insufficiency (main cause of premature death). Our long-term goal is to develop a gene therapy treatment for FRDA based on a single injection of an Adeno Associated Virus (AAV) coding for the correcting agents. We have already showed that our approach using the CRISPR technology, where an enzyme named SpCas9 permits to cut DNA before and after GAA repeat to induce a permanent deletion. This restores the frataxin protein level. The present project aims to optimize the AAV to improve the treatment while avoiding mutations of other genes. We will also investigate a new method (named Hara-Kiri) to avoid a sustained expression of a smaller Cas9 (CjCas9) to reduce off-target effect mutations and prevent a possible immune response. We will conduct in vivo experiments in a mouse model to accumulate data for an eventual Phase I clinical study. Developing an in vivo gene editing therapy approach for monogenic diseases is highly significant and medically relevant. The impact of a single gene therapy treatment for these patients will greatly enhance their quality of life and reduce the cost associated with long-term health care management.