The successful candidate will join the Gene Therapy for MSUD group, co-led by Drs. Clément Pontoizeau and Manuel Schiff and will work in close collaboration with Dr. Giuseppe Ronzitti (INSERM UMRS_951 INTEGRARE).

Scientific background and project :

Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by deficiency of the branched-chain ketoacid dehydrogenase (BCKD) complex, leading to toxic accumulation of branched-chain amino acids. Up to 85% of MSUD patients have variants in BCKDHA or BCKDHB genes. Current therapies rely on life-long dietary restriction and, in selected cases, liver transplantation; however, these approaches remain burdensome and do not fully prevent long-term neurological complications.

We established that neonatal AAV gene therapy (GT) in MSUD mouse models 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.

We already obtained robust and reproducible data with a new generation of AAV vectors (coll. Dr G. Ronzitti, Genethon, Evry) achieving sustained phenotypic recue and biochemical correction at low dose in a first MSUD mouse model.

The aim of this 2-year research project is to complete the evaluation of such strategy and to replicate it in a second MSUD mouse model, providing essential data to move toward a clinical trial.

Objectives of the position :

The recruited engineer will play a central role in advancing this program toward clinical translation by :

• Performing and coordinating AAV gene therapy experiments in MSUD mouse models (in vivo experimentation) ;

• Performing molecular and biochemical analyses (vector genome copy number analysis, RT-PCR, western blot analysis, enzymatic activity, amino acids measurement by LC-MS/MS) ;

• Contributing to data analysis, figure preparation, and drafting of scientific manuscripts and reports ;

• Working closely with researchers, clinicians, and translational partners in a highly collaborative research environment.

Profile and skills required :

• Master’s degree or engineering degree (or equivalent) in molecular biology, biotechnology, biomedical sciences, or a related field ;

• Demonstrated hands-on experience in molecular biology and animal experimentation; prior experience in animal experimentation, in AAV biology (if possible) or gene therapy (if possible) is highly desirable ;

• Strong organizational skills, scientific rigor, and ability to work both independently and within a multidisciplinary team ;

• High motivation for translational research in rare genetic diseases.

Contract and practical information :

• Contract type: Fixed-term contract (CDD, INSERM) ;

• Duration: 24 months ;

• Salary: According to INSERM salary scale and professional experience ;

• Starting date: First quarter of 2026.

Application :

Applications should include a curriculum vitae and a brief motivation letter