Gene therapy offers new hope for children with metachromatic leukodystrophy

Abstract

Metachromatic leukodystrophy (MLD) is a rare, progressive lysosomal storage disease caused by mutations in the gene encoding arylsulfatase A (ARSA), causing disease in the central and peripheral nervous systems. MLD presents in toddlers (late infantile disease) or in children (juvenile disease) with gait disturbances, loss of developmental milestones, and cognitive decline, leading to death in childhood. It is frequently not diagnosed until the later symptomatic phase when it is too late to intervene. Haematopoietic stem-cell transplantation (HSCT) from allogeneic donors has been used with mixed results. Although HSCT can slow progression of disease in the central nervous system, it does not prevent progression in the peripheral nervous system. HSCT is also associated with risks of graft-versus-host disease and treatment-related toxicity. 1 Boucher AA Miller W Shanley R et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J Rare Dis. 2015; 10: 94 Crossref PubMed Scopus (66) Google Scholar , 2 Wolf NI Breur M Plug B et al. Metachromatic leukodystrophy and transplantation: remyelination, no cross-correction. Ann Clin Transl Neurol. 2020; 7: 169-180 Crossref PubMed Scopus (11) Google Scholar , 3 Beschle J Döring M Kehrer C et al. Early clinical course after hematopoietic stem cell transplantation in children with juvenile metachromatic leukodystrophy. Mol Cell Pediatr. 2020; 7: 12 Crossref PubMed Google Scholar , 4 Vander Lugt MT Chen X Escolar ML et al. Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders. Blood Adv. 2020; 4: 3041-3052 Crossref PubMed Scopus (3) Google Scholar Additionally, small trials of intrathecal gene therapy in mice or humans did not result in improvement in symptoms of clinical disease. 5 Miyake N Miyake K Sakai A Yamamoto M Suzuki H Shimada T Treatment of adult metachromatic leukodystrophy model mice using intrathecal administration of type 9 AAV vector encoding arylsulfatase A. Sci Rep. 2021; 1120513 Crossref PubMed Scopus (1) Google Scholar Thus, new therapeutic approaches are desperately needed. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded accessTreatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy. Full-Text PDF Open Access