OR13
Gene Therapy For Spinocerebellar Ataxia 7 : Restoring Cholesterol Metabolism
E G Banchi ¹ J Dégardin-Chicaud ² A Lamazière ³ E Audouard ¹ C Sayetta ¹ B Faye ¹ L Stimmer ¹ A Prigent ¹ J Droesbeke ¹ N Sarrazin ¹ A Baskaran ¹ D Langui ¹ M Simonutti ² S Picaud ² N Cartier ¹ A Durr ¹ F Piguet ¹ M Latouche ¹
1: Institut du Cerveau et de la Moelle épiniere 2: Institut de la Vision 3: Hôpital Saint Antoine, Paris
Brain cholesterol is almost exclusively synthesized in situ and defects in this metabolism may contribute to neurodegenerative disease such as Alzheimer’s (AD) and Huntington’s (HD). Previous data in rodent and human patients have demonstrated the impairment in AD and HD of CYP46A1, the brain-specific rate-limiting enzyme in the degradation of cholesterol. In AD and HD mouse models restoring the CYP46A1 enzyme is neuroprotective.Like HD, Spinocerebellar ataxias (SCAs) are caused by the expansion of a translated CAG (polyQ) in the respective proteins. SCA7 is caused by pathological repeat (34 to >200 polyQ) in the ATXN7 protein and characterized by cerebellar ataxia with retinal degeneration.
Our work aims to investigate the role of brain cholesterol metabolism dysfunction in the ATXN7 140Q Ki mouse model and evaluate if overexpressing CYP46A1 enzyme thanks to an AAVPHP.eB using intravenous delivery could cure or alleviate SCA7 pathology.
To assess the gene therapy potential on the SCA7 disease progression, we assessed monthly a number of parameters characterizing the SCA7 phenotype including body weight, locomotion, motor skills and vision. After 9 months, at the end of the behavioural analysis, we performed electrophysiological analysis of neuromuscular function and vision prior to brain collection for further histology, biochemistry and lipidomic analysis. The first results show that overexpression of CYP46A1 leads to increasing the level of intermediate compounds of the brain cholesterol metabolism while improving locomotion, motor skills, and neuromuscular reflexes.