Substrate Reduction Therapies for Mucopolysaccharidoses

Joanna      Jakobkiewicz-Banecka; Ewa      Piotrowska; Magdalena      Gabig-Ciminska; Elzbieta      Borysiewicz; Monika      Slominska-Wojewodzka; Magdalena      Narajczyk; Alicja      Wegrzyn; Grzegorz      Wegrzyn

Abstract

Mucopolysaccharidoses (MPS) are inherited metabolic disorders, caused by mutations leading to dysfunction of one of enzymes involved in degradation of glycosaminoglycans (GAGs) in lysosomes. Due to their impaired degradation, GAGs accumulate in cells of patients, which results in dysfunction of tissues and organs, including the heart, respiratory system, bones, joints and central nervous system. Depending on the kind of deficient enzyme, 11 types and subtypes of MPS are currently recognized. Although enzyme replacement therapy has been developed for 3 types of MPS (types I, II and VI), this treatment was found to be effective only in management of somatic symptoms. Since all MPS types except IVA, IVB and VI are characterized by various problems with functioning of the central nervous system (CNS), a search for effective treatment of this system is highly desirable. Recent discoveries suggested that substrate reduction therapy may be an efficient method for treatment of MPS patients, including their CNS. In this review, different variants of this therapy will be discussed in the light of recently published reports.

Keywords: mucopolysaccharidoses, lysosomal storage diseases, substrate reduction therapy, gene expression-targeted isoflavone therapy, siRNA, shRNA, glycosaminoglycans (GAGs), large biomolecules, central nervous system (CNS), neurodegenerative diseases, genetic disorders, symptomatic treatment of patients, Sanfilippo disease, hematopoietic stem cells', untreated animals, cognitive functions