Gene therapy for ALS by restoring neuronal cholesterol metabolism – NeuroCYP

phase I/II.
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease, characterized by muscular paralysis due to the loss of motoneurons in the spinal cord, motor cortex and the brainstem. The majority of cases are sporadic (90%) and familial forms are associated with different genes C9ORF72, SOD1... Currently, no treatment stops the progression of the disease and the patients die within 3 to 5 years after symptom onset. Therefore it is crucial to develop new therapeutic approaches especially for symptomatic patients. Our laboratory has demonstrated therapeutic efficacy of CYP46A1 overexpression, an neuronal enzyme from the cholesterol pathway, in several neurodegenerative diseases.
The aim of my project is to perform all the preclinical studies to validate a gene therapy strategy for Amyotrophic Lateral Sclerosis (ALS) to restore the neuronal cholesterol mechanism, which is affected in the disease, through the delivery in motoneurons of its key enzyme : CYP46A1 thanks to an AAV vector. I just established the proof of concept of this approach in the severe mouse model of the pathology (SOD1G93A). A unique intravenous delivery of AAV-CYP46A1 not only prevent but also rescue motor abnormalities and histopathological of ALS. My aims are, 1 ) Complete the proof of concept, that I already established in the SOD1 model, in C9ORF72 model this confirming that this approach could be efficiently applied in different forms (genetic and potentially sporadic) of the disease, and perform a dose response study in SOD1G93A mouse model 2) Decipher the molecular, cellular and metabolic mechanisms by which AAV-CYP46A1 targeted to motoneurons may rescue the pathophysiological hallmarks of ALS and 3) perform the translational steps towards clinical phase I/II application: optimize the delivery of the AAV-CYP46A1 vector in non-human primates to efficiently target cortical and spinal motoneurons, define the clinical protocol and demonstrate tolerance.