title: Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders.
abstract: Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, efforts have been mainly targeting the functional loss of the enzyme, by injection of a recombinant formulation, in a process called enzyme replacement therapy (ERT), with no impact on neuropathology. This ineffectiveness, together with its high cost and lifelong dependence is amongst the main reasons why additional therapeutic approaches are being (and have to be) investigated: chaperone therapy; gene enhancement; gene therapy; and, alternatively, substrate reduction therapy (SRT), whose aim is to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the levels of biosynthesis of the accumulating substrate(s). Here we review the concept of substrate reduction, highlighting the major breakthroughs in the field and discussing the future of SRT, not only as a monotherapy but also, especially, as complementary approach for LSDs.
authors.affiliation: Department of Human Genetics, Research and Development Unit, National Health Institute Doutor Ricardo Jorge, Rua Alexandre Herculano, 321 4000-055 Porto, Portugal. francisca_coutinho@yahoo.com.
authors.forename: Maria Francisca
authors.initials: MF
authors.lastname: Coutinho
authors.affiliation: Department of Human Genetics, Research and Development Unit, National Health Institute Doutor Ricardo Jorge, Rua Alexandre Herculano, 321 4000-055 Porto, Portugal. juliana.santos@insa.min-saude.pt.
authors.forename: Juliana Inês
authors.initials: JI
authors.lastname: Santos
authors.affiliation: Department of Human Genetics, Research and Development Unit, National Health Institute Doutor Ricardo Jorge, Rua Alexandre Herculano, 321 4000-055 Porto, Portugal. sandra.alves@insa.min-saude.pt.
authors.forename: Sandra
authors.initials: S
authors.lastname: Alves
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D056947:Enzyme Replacement Therapy; D005776:Gaucher Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D019833:Genistein / Q000627:therapeutic use; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009083:Mucopolysaccharidoses / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: D017485:1-Deoxynojirimycin; C059896:miglustat; D019833:Genistein
keywords: Gaucher disease (GD); Niemann-Pick type C (NPC); Sanfilippo syndrome); combination therapy; eligluistat tartrate; genistein; miglustat; mucopolysaccharidosis type III (MPS III; substrate reduction therapy (SRT)