Article Text
Abstract
Introduction Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage diseases caused by different enzyme deficiencies that lead to accumulation of glycosaminoglycans (GAGs) in lysosomes and the extracellular matrix. This storage-induced inflammation is a key driver of cytopathology in MPS, and pharmacological immunomodulation can improve brain, cartilage and bone symptoms in rodents. As the approved enzyme replacement therapy cannot stop the progression of CNS involvement and several other symptoms, we develop a rational for personalized treatment to address the unmet clinical need in MPS patients.
Methods First, we conducted comprehensive literature reviews on MPS type specific inflammatory immune response and on the safety and efficacy of Adalimumab, Infliximab, Abatacept, Alemtuzumab, Anakinra. Second, by expert consensus top candidates for innovative personalized drug repurposing in MPS patients were identified and ranked.
Results The key process is the upregulation of toll-like receptor-4 (TLR4) pathway induced by the accumulation of heparan sulfate (HS) in MPS type I, II and III. This and other relevant mech-anisms indicate TNF-alpha and IL-1 as most promising targets. Systematic analysis of the clinical pharmacology of all relevant candidates and several expert focus group meetings identified Anakinra, Adalimumab, Cladribine and Abatacept as top candidate’s dependent on the individual clinical situation.
Conclusions These results provide the rational for individual treatment trials (ITTs) with the aim to evaluate immunomodulatory molecules, repurposed in MPS. Furthermore, they will – together with the results of the ITTs – be utilized for the development of a decision tool for the personalized treatment of unmet clinical needs in these patients.