Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease and is characterized by the progressive loss of upper and lower motor neurons, leading to paralysis and death. Defects in brain cholesterol metabolism contribute to neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD) and Spinocerebellar ataxias (SCAs). Beside contributing to myelin compartment, cholesterol is a critical component of membranes where it plays key structural and functional roles. Cholesterol cannot cross the blood brain barrier (BBB) and is synthesized in situ. Cholesterol 24-hydroxylase (CYP46A1) ensures the conversion of cholesterol into 24S-hydroxycholesterol that can freely cross the BBB. This key neuronal enzyme of brain cholesterol metabolism plays a crucial role in maintaining brain cholesterol homeostasis and is a major neuronal stress response in conditions with oxidative stress, like ageing or toxic protein accumulation.

We previously demonstrated in the laboratory that overexpression of CYP46A1 through AAV-encoding CYP46A1 delivery, efficiently rescued clinical and neuropathological hallmarks of mouse models of AD; HD and SCA3. CYP46A1 gene therapy is able to restore deficient autophagy process in these diseases and clearance of protein aggregates (amyloid, huntingtin, ataxin 3). This suggest us that CYP46A1 could be a relevant therapeutic target for ALS to improve stress response, in the clearance of toxic aggregated proteins, synaptic transmission, inflammation and finally neuronal survival.    Therefore, we hypothesized that CYP46A1 could be relevant for a therapy in ALS to target both familial and sporadic forms of ALS independently from their genetic origin.
In the severe SOD1ᴳ⁹³ᴬ model, we overexpressed CYP46A1 using a an AAVPHP.eB. As a first step, we confirmed that the AAV has a specific tropism for the CNS and especially motoneurons. Secondary, we demonstrated a significant and prolonged motor rescue of animals treated pre or post-symptomatically, but also a preventive effect on motoneuron degeneration, myelin loss, compared to untreated animals but also a significant rescue of muscle and neuromuscular junction phenotype as well as a complete rescue of misfolded SOD1 protein aggregation.
More recently, we demonstrated that CYP46A1 overexpression is also efficient in another model of the ALS: the C9ORF72 expansion model with a prevention/correction of the behavior abnormalities. Results on both models will be presented.