Improving Diagnosis and Treatment Outcomes in Mucopolysaccharidoses

UoM administered thesis: Phd

  • Authors:
  • Arunabha Ghosh


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.


Original languageEnglish
Awarding Institution
Award date1 Aug 2019