Metachromatic leukodystrophy (MLD) is a neurodegenerative disease caused by a defect in the activity of the enzyme Arylsulfatase A (ARSA), leading to the accumulation of sulfatides in cells of the central and peripheral nervous system, especially cells that make the myelin, but also neurons. The late infantile form, the most severe and most frequent form, begins around 1-2 years of age. It is characterised by very rapid motor and cognitive degradation leading to bedridden condition and early death. Today there is no treatment for this form of the disease when children are symptomatic.

Intracerebral gene therapy may allow rapid and sustained expression of the ARSA enzyme in the brain, a necessary condition to stop the neurodegenerative process in a timely manner. We have developed a clinical protocol for the intracerebral administration of a drug vector containing the therapeutic gene ARSA (AAVrh.10 / ARSA). After validating the effectiveness of this protocol in disease model mice, we optimised and validated the neurosurgical procedure in primates to allow simultaneous delivery of the drug vector to 12 brain regions. We have shown that injection of the AAVrh.10 / ARSA vector results in significant overexpression of ARSA throughout the primate brain without any deleterious effects.

We have obtained from the authorisations necessary to start a phase I-II clinical trial (tolerance and efficacy) in affected children from the ANSM (National Agency for the Safety of Medicines and Health Products) and the committee for the protection of persons, MLD.  This trial, currently open for recruitment, will include five children (aged 6 months to 5 years inclusive) with early forms of MLD (late infantile, precocious juvenile), at the very beginning of their disease. Safety and efficacy parameters will be evaluated for 2 years, a period which should be sufficient to assess the safety and therapeutic efficacy of this treatment. The first two patients were included in this clinical protocol and received the drug vector intracerebrally.