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Encapsulated cells as an enzyme replacement therapy for metachromatic leukodystrophy.

Emilie Audouard,Florine Chereau,Camille Lupiet,Charlotte Mansat,L. Roger,Pauline Libert,E. Banchi,Nicolas Khefif,D. Farabos,A. Lamazière,Marie-Anne S. Colle,Marc Folcher,Caroline Sevin,Françoise Piguet

Published 2025 in Journal of Controlled Release

ABSTRACT

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by an inherited deficiency of arylsulfatase A (ARSA) and characterized by accumulation of sulfatides in both glial cells and neurons resulting in myelin degeneration in the central and peripheral nervous systems, neuronal degeneration and neuroinflammation. Currently, no effective treatment is available for patients once symptoms are already present. Libmeldy©, an Ex vivo gene therapy, is the gold standard for pre-symptomatic patients with late-infantile and early juvenile MLD, and early symptomatic patients with early-juvenile MLD. Here, we investigated an innovative approach to deliver the recombinant ARSA enzyme by encapsulated-cell therapy. A cell-based device is capable of continuously delivering human ARSA compared to weekly intrathecal delivery of recombinant ARSA, which is under clinical evaluation in a phase II-III clinical trial. Two constructs of genetically engineered cells have been tested to determine which one could target more efficiently the central nervous system. Importantly, a dose response evaluation has been done with 2 doses (cells number loaded) to evaluate the best therapeutic effect. MLD mice were implanted at 6 months of age once disease is well established. The device biocompatibility as well as the therapeutic efficacy have been evaluated 3 months after implantation. The device was well tolerated in animals. Moreover, we demonstrate a correction of sulfatide storage and significant improvement of neuroinflammation in the CNS of all treated mice. All these data establish a strong rational to propose cell-based device therapy in symptomatic MLD patients.

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