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.

Keywords:

• metachromatic leukodystrophy
• arylsulfatase A
• enzyme replacement therapy
• gene therapy
• enzyme enhancement therapy
• small molecules

Acknowledgments

We are grateful for our collaborators including Marc Ferrer PhD and his group at the NIH-Chemical Genomic Center (NCGC) for the instrumental assistance in the development of high-throughput screening cell-based assays targeting different lysosomal enzymes. We are also thankful for our collaborators who donated cell lines including Dr Hirokazu Furuya MD, PhD, neurologist from NHO Omuta Hospital, Omuta, Fukuoka, Japan.

Disclosure

Shilpa Patil is partially supported by National MPS Society. Gustavo Maegawa is currently supported by grants NIH-NIMH 1R03MH098689 and NIH-NINDS 1R01NS079655. Dr Maegawa also receives research grants from the National MPS Society and received research grants from the National Tay-Sachs Disease and Allied Diseases Association. Dr Maegawa receives research funds for clinical and educational studies from Genzyme Therapeutics Ltd, Biomarin Pharmaceutical Inc, Protalix Biotherapeutics Inc, and Shire HGT. The authors declare no other conflicts of interest in this work.