Maple syrup urine disease (MSUD or branched chain ketoacid dehydrogenase deficiency) is a rare autosomal recessive metabolic disease with unmet needs. 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 promoter1. Importantly, our data suggest that the targeting of organs other than liver may lead to therapeutic efficacy especially in the neonatal period, offering to test new strategies associated with safer tissue targeting and the potential use of lower doses. Testing MSUD AAV GT in adult mice represents our next challenge, as in a neonatal setting, AAV-mediated liver-directed GT is likely to lose efficacy overtime due to the non-integrating nature of AAV, precluding drawing conclusions about its potential efficacy in adults.
The present project aims at developing these new strategies and overcoming the above-mentioned challenge. We will i) develop an innovative muscle-directed AAV GT in order to detarget the liver while enhancing muscle targeting, to improve the safety of neonatal gene therapy at high dose, ii) develop an inducible Bckdha-/- mouse in order to test AAV GT at adult age, with lower doses, using either a liver-specific or other tissue-specific promoters.
The present project will optimise MSUD AAV GT to move towards its clinical translation. It will be developed under the supervision of Drs. Clément PONTOIZEAU and Manuel SCHIFF co-leaders of the gene therapy MSUD group within the laboratory of Mitochondrial Disease Genetics lead by Dr. Agnès RÖTIG, UMRS_1163, Imagine Institute and Necker-Enfants-Malades Hospital, Paris. Imagine institute (Institut des Maladies Génétiques), UMRS_1163 is an INSERM unit with up to 1000 researchers in 20+ research teams dedicated to rare genetic disorders. This project will be conducted in tight collaboration with Dr. Giuseppe Ronzitti, researcher at UMRS_951 ‘’INTEGRARE’’ unit.
Applicants should have a PhD and a strong background in AAV biology and expertise in animal models and molecular biology. Motivated candidates with creative and innovative skills, as well as ability to teamwork are especially encouraged to apply. Applications, including a motivation letter and detailed curriculum vitae should be sent Drs Clément PONTOIZEAU and Manuel SCHIFF (firstname.lastname@example.org and email@example.com).
18 months (CDD), salary will be calculated based on applicant’s experience.
Starting Date: 1st quarter of 2023
- Pontoizeau C, Simon-Sola M, Gaborit C, et al (2022) Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice. Nat Commun 13:3278. https://doi.org/10.1038/s41467-022-30880-w