Developing therapeutic approaches for metachromatic leukodystrophy

Abstract

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood–brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.

Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report

“…While most patients ultimately experienced neurologic decline following transplant, HSCT appears to more favorably impact the trajectory of natural progression of cognitive compared to motor dysfunction. Treatment with HSCT should be carefully considered for patients with MLD, as investigations into other treatment modalities aimed at improving outcomes continue [ 41 , 43 , 44 ].…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…The lack of a complete recapitulation of the clinical and pathological MLD phenotype led to the generation of the Arsa (−/−) mice with the addition of neural cells overexpressing the sulfatide synthesizing enzymes, including UDPgalactose: ceramide galactosyltransferase (CGT) and cerebroside sulfotransferase (CST). These CGT/Arsa (−/−) and CST/Arsa (−/−) mice had increased sulfatide storage in myelin-forming cells, resulting in axonal degeneration leading to the development of neurological symptoms similar to MLD (Patil and Maegawa, 2013). 3.…”

“…While many mouse models of LSDs accurately reflect the human symptomatology of the disease they model, there are a number of examples in which generated models fall short. For example, Arsa (−/−) MLD mice show mild neurological symptoms that are only observed by the end of a normal lifespan, and fail to show sulfatide accumulation and demyelination (Patil and Maegawa, 2013). These differences may be explained by the fundamental differences of mice and human development, particularly in regards to neurodevelopment (Lin et al, 2014).…”

“…Attempts to generate a more 'authentic' human model may consequentially produce a mouse model similar to the human disease, but nonetheless artificial. For example, Arsa (−/−) mice with neural cells overexpressing the sulfatide synthesizing enzyme CGT or CST have more similar pathology to human MLD patients (Patil and Maegawa, 2013). Furthermore, the artificial nature of 'knockout' systems sometimes trigger compensatory mechanisms not seen in human disease (El-Brolosy and Stainier, 2017).…”

Late infantile metachromatic leukodystrophy: Clinical manifestations of five Taiwanese patients and Genetic features in Asia

“…Metachromatic leukodystrophy (MLD) is a rare autosomal recessive inherited disease, which is caused by a deficiency in the enzyme activity of Arylsulfatase A (ARSA). ARSA is required for the hydrolysis of sulfated glycosphingolipids, which are also known as sulfatides, and its deficiency results in excessive accumulation of sulfatide in myelin in the nervous system, the bile ducts of the liver, and the distal tubules of the kidney [ 1 – 3 ]. ARSA deficiency results from a mutation in the ARSA gene, which spans 3.2 kb of genomic DNA on chromosome 22q13 [ 2 , 4 ].…”