Gene therapy for metachromatic leukodystrophy

Abstract

Summary Leukodystrophies are rare white matter genetic disorders of the central nervous system (CNS) with progressive neurologic deterioration. One approach to the treatment of leukodystrophies is by gene therapy. Using metachromatic leukodystrophy (MLD), a leukodystrophy resulting from deficiency of a lysosomal catabolic enzyme arylsulfatase A (ARSA) as the example, this review is focused on the current status of preclinical and clinical development of gene therapy as a viable treatment option for leukodystrophies. In MLD, mutations in the ARSA gene result in excess buildup of sulfatides, which triggers apoptosis of glia and neurons. The disease is characterized by severe cerebral demyelination and atrophy, with progressive loss of oligodendrocytes, neurons and Schwann cells. The optimal therapy for MLD would provide persistent and high level expression of ARSA in the CNS. Gene therapy using adeno-associated virus (AAV) is an ideal choice for clinical development as it provides the best balance of potential for efficacy with a reduced safety risk profile. In this review, we have summarized preclinical data that support the use of a gene therapy with the AAVrh.10 serotype for clinical development as a treatment for MLD.

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

“…Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder, caused by mutations in the ARSA gene coding for arylsulfatase A (Gieselmann & Krageloh-Mann, 2010;Kohlschutter, 2013;Rosenberg, Kaminsky, Aubourg, Crystal, & Sondhi, 2016;van Rappard, Boelens, & Wolf, 2015). The storage products consist of sulfatide and are found not only in myelinating glia of both CNS and peripheral nerves (PNS), astrocytes and neurons but also in phagocytic cells of the nervous system (van Rappard et al, 2015).…”

“…The storage products consist of sulfatide and are found not only in myelinating glia of both CNS and peripheral nerves (PNS), astrocytes and neurons but also in phagocytic cells of the nervous system (van Rappard et al, 2015). Outside the nervous system, many other organs display the storage products, and the gallbladder is functionally affected (Kohlschutter, 2013;Rosenberg et al, 2016;van Rappard et al, 2015). Dependent on the exclusively recessive mutations, three variants are known, comprising late-infantile, juvenile, and adult onset type.…”

“…Outside the nervous system, many other organs display the storage products, and the gallbladder is functionally affected (Kohlschutter, 2013;Rosenberg et al, 2016;van Rappard et al, 2015). The most common late-infantile form presents with delayed development of motor skills and spasticity, progressive loss of vision, seizures, paralysis, dementia, and premature death (Rosenberg et al, 2016), thus resembling some storage disorders not predominantly related to myelin components, like CLN3 (see below). The most common late-infantile form presents with delayed development of motor skills and spasticity, progressive loss of vision, seizures, paralysis, dementia, and premature death (Rosenberg et al, 2016), thus resembling some storage disorders not predominantly related to myelin components, like CLN3 (see below).…”

“…Dependent on the exclusively recessive mutations, three variants are known, comprising late-infantile, juvenile, and adult onset type. Enzyme replacement, stem cell transplantation, gene therapies, or the combination of the latter two are possible future treatment options (Biffi et al, 2013;Kohlschutter, 2013;Rosenberg et al, 2016). Enzyme replacement, stem cell transplantation, gene therapies, or the combination of the latter two are possible future treatment options (Biffi et al, 2013;Kohlschutter, 2013;Rosenberg et al, 2016).…”

“…Dependent on the exclusively recessive mutations, three variants are known, comprising late-infantile, juvenile, and adult onset type. The most common late-infantile form presents with delayed development of motor skills and spasticity, progressive loss of vision, seizures, paralysis, dementia, and premature death (Rosenberg et al, 2016), thus resembling some storage disorders not predominantly related to myelin components, like CLN3 (see below). Enzyme replacement, stem cell transplantation, gene therapies, or the combination of the latter two are possible future treatment options (Biffi et al, 2013;Kohlschutter, 2013;Rosenberg et al, 2016).…”