Emerging treatment options for the mucopolysaccharidoses

Roberto Giugliani,^1–6 Andressa Federhen,^1,4 André Anjos da Silva,^1,5 Camila Matzenbacher Bittar,^1,5 Carolina Fischinger Moura de Souza,¹ Cristina Brinckmann Oliveira Netto,¹ Fabiana Mayer,^2,7 Guilherme Baldo,^1,2,8 Ursula Matte<sup>1–5

1</sup>Medical Genetics Service, ²Gene Therapy Center, Hospital de Clínicas (HCPA), Porto Alegre, RS, Brazil; ³Department of Genetics, ⁴Postgraduate Program in Child and Adolescent Health, ⁵Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; ⁶National Institute of Population Medical Genetics (INAGEMP), Porto Alegre, RS, Brazil; ⁷Fundação Estadual de Pesquisa Agropecuária (FEPAGRO), Eldorado do Sul, RS, Brazil; ⁸Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

Abstract: The mucopolysaccharidoses (MPS) are a group of diseases arising from one of eleven different enzyme defects, each one affecting one single step of the degradation pathway of glycosamynoglycans. Several developments in the understanding of the MPS have occurred since the first clinical report about their occurrence in 1917: the nature of the storage product was recognized, a useful biomarker (mucopolysacchariduria) was developed, the enzyme defects became identified, and the gene defects were elucidated. The first successful treatment for MPS diseases was bone marrow transplantation, which was introduced for the therapy in 1980. Over the last decade, a whole new set of therapeutic approaches have become available or are currently in development to address MPS. Intravenous enzyme replacement therapy, already approved for MPS I, II, and VI, will possibly be available for MPS IVA and for MPS VII within the next few years. Intrathecal enzyme replacement therapy (tested in animals and already reported in a few patients) may become a tool to treat or prevent the central nervous system (CNS) manifestations which occur in several MPS. Substrate inhibition therapy using small molecules which cross the blood–brain barrier is also being tested for MPS types with CNS manifestations. In vitro studies point out that chaperones may also be of therapeutic value when the main cause is protein misfolding and retention at the endoplasmic reticulum. Stop-codon read-through strategy has been tried in preclinical studies with MPS models caused by nonsense mutations. Preclinical studies assessing gene therapy also show quite encouraging results, and this modality of treatment is now moving toward clinical development. The use of neural stem cells in MPS types which have CNS involvement is also promising. It is important to point out that MPS diseases are hard to treat, and demand specific therapies with a broad range of supportive measures. An additional challenge arises from the high cost of these technology intensive approaches, and this needs to be addressed if the treatments are to become widely available. Finally, since there is evidence that early diagnosis followed by early treatment considerably improves the health outcomes for these patients, newborn screening is becoming increasingly important for the early diagnosis of affected patients.

Keywords: mucopolysaccharidoses, glycosaminoglycans, treatment, enzyme replacement therapy, gene therapy, lysosomal diseases