OPTImisation of MSUD AAV gene therapy – OPTIMSUD

Maple syrup urine disease (MSUD or branched chain ketoacid dehydrogenase deficiency) is a rare autosomal recessive metabolic disease with unmet needs. 80% of MSUD patients have variants in BCKDHA or BCKDHB genes. MSUD life-long dietary therapy is difficult to maintain and does not prevent long-term neuropsychiatric impairments. Liver transplant, while correcting only 10% of the whole-body enzyme activity is therapeutic. The low levels of activity required and the presence of unequivocal biomarkers were rationales for testing AAV liver-directed gene therapy (GT) in neonatal early lethal MSUD mice. We established that neonatal GT was curative when using a ubiquitous promoter while efficacy remained limited with a liver-specific promoter. The data obtained in this fundamental proof-of-concept study have limitations. First, the dose (1014 vg/kg) used for AAV GT with a constitutive promoter, is not readily translatable to human due to potential risk of acute liver toxicity. Lower vector doses or safer tissue targeting should be preferable. Importantly, our data suggest that the targeting of organs other than liver may lead to therapeutic efficacy especially in the neonatal period. Second, AAV-mediated liver-directed GT in a neonatal setting is likely to lose efficacy overtime due to the non-integrating nature of AAV, precluding drawing conclusions about its potential efficacy in adults.
OPTIMSUD aims at developing strategies overcoming the above-mentioned limitations. We will i) develop an innovative muscle-directed AAV GT in the Bckdha-/- mouse in order to detarget the liver while enhancing muscle targeting, to improve the safety of neonatal gene therapy at high dose, ii) test different transgene constructs and capsid/promoter combinations to reduce the minimal efficacy dose and iii) apply the same strategy in the Bckdhb-/- mouse.
In conclusion, the OPTIMSUD collaborative project will optimise MSUD AAV GT to move towards clinical translation.