Mucopolysaccharidoses (MPS) are a heterogenous group of disorders caused by inherited deficiencies of enzymes involved in glycosaminoglycan degradation. Two such disorders, MPS I and MPS III, present distinct treatment challenges. In MPS I, significant areas of unmet need remain despite the existence of two therapies: enzyme replacement therapy (ERT) and haematopoietic stem cell transplantation (HSCT), the latter being the treatment choice in severe MPS I (Hurler syndrome). Several strategies to optimise diagnosis and treatment are considered: (1) the safety and utility of combined ERT and HSCT, a frequently used, though not universal, treatment approach; (2) mitigation of the antibody response to ERT, which may negatively impact treatment efficacy; (3) the development of genotype-phenotype relationships that would be relevant for the implementation of newborn screening, and could enable earlier initiation of therapy and improve outcomes. MPS III is a predominantly neurological disease with no existing treatment. The efficacy of genistein aglycone, a potential substrate reduction therapy, was investigated in MPS III patients. In a retrospective review of 81 MPS I patients who received peri-transplant ERT, overall survival was 88% and engrafted survival was 81% (median follow-up 46 months). Improvement in cardiopulmonary disease status during ERT enabled selected individuals to tolerate full intensity conditioning. An open-label study of prophylactic immune tolerance induction using methotrexate in three MPS I Hurler individuals found that one or three weeks of oral methotrexate did not prevent high titre anti-drug antibody responses. However, in an MPS I mouse model, two courses of an anti-CD4 monoclonal antibody prevented antibody responses to ERT in seven out of eight mice (87.5%). Analysis of genotypes and phenotypic severity in a cohort of 286 MPS I patients identified 63 IDUA variants, of which 20 were novel, and associations with phenotypic severity were assigned for all but six. A total of 37 variants were only identified in a single individual or family, but this accounted for only 13% of individuals. In 57% of individuals, both alleles were one of nine common variants. A double-blinded, randomised, placebo-controlled clinical trial of high dose genistein aglycone (160mg/kg/day) in MPS III found that 12 months of genistein did not result in a significantly lower concentration of cerebrospinal fluid heparan sulfate than placebo (p=0.26), and the size of reduction (5.5%) was not clinically meaningful. No deviation from natural history in neuropsychological measures was observed. These findings suggest potential approaches to improving diagnosis and treatment. Combined ERT and HSCT in MPS I has clinical utility for selected high risk individuals, though patients are known to develop anti-drug antibodies. These could be mitigated by immune tolerance induction, and the efficacy of a non-depleting anti-CD4 monoclonal antibody should be investigated in humans. The majority of MPS I individuals in the UK have well-characterised IDUA variants for which phenotypic severity could be predicted based on genotype, enabling selection of appropriate therapy (ERT or HSCT) following newborn screening. Successful disease-modifying therapy for MPS III remains elusive, but the genistein study contributes to the pool of natural history and informs clinical trial design for future therapies.
