Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storage-induced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).
Mucopolysaccharidoses (MPS) are a group of rare, heterogeneous, lysosomal storage disorders. Patients show a broad spectrum of clinical features with a substantial unmet medical need. Individual treatment trials (ITTs) might be a valid, time- and cost-efficient way to facilitate personalized medicine in the sense of drug repurposing in MPS. However, this treatment option has so far hardly been used—at least hardly been reported or published. Therefore, we aimed to investigate the awareness and utilization of ITTs among MPS clinicians, as well as the potential challenges and innovative approaches to overcome key hurdles, by using an international expert survey on ITTs, namely, ESITT. Although 74% (20/27) were familiar with the concept of ITTs, only 37% (10/27) ever used it, and subsequently only 15% (2/16) published their results. The indicated hurdles of ITTs in MPS were mainly the lack of time and know-how. An evidence-based tool, which provides resources and expertise needed for high-quality ITTs, was highly appreciated by the vast majority (89%; 23/26). The ESITT highlights a serious deficiency of ITT implementation in MPS—a promising option to improve its treatability. Furthermore, we discuss the challenges and innovative approaches to overcome key barriers to ITTs in MPS.
IntroductionMucopolysaccharidoses (MPS), comprise a group of rare chronically debilitating metabolic diseases and associated with reduced life expectancy and a substantial unmet clinical need. Current research directs towards a number of new treatment targets and strategies. Individual treatment trials (ITT) could make these options rapidly available to patients. Based on scientific publication, this is hardly used. We assess the utilization of and relevant barriers to ITT in MPS as well as potential solutions.MethodsPhase 1 was done with 5 international top experts. After this interim analysis, the survey will be rolled out to a broader group of experts.ResultsFive MPS experts from Austria, Brazil, Germany and Italy have been enrolled. In total these clinicians manage about 350 MPS patients. Only three experts ever ran 1–3 numbers of ITT in MPS patients, solely MPS type II (n=2) and VI (n=1), summing up to a total of five ITTs, which is about 1.4% of their patients. The treatments used in ITTs comprise Montelukast, THC, Curcuma and a viral vector with transgene. As barriers for a wider use of ITTs, the im-practicability for implementation (n=1) and the insufficient training in ITT (n=1) have been indicated. All experts consider it highly likely that a decision analysis tool increases the use of ITT in MPS.ConclusionsITT are used in about 1% of MPS patients. This seems extremely low, considering the commonness of off label use in children with severe conditions, the high unmet medical need in MPS and the number of research results, which indicate various promising repurposing strategies. This interim analysis already demonstrates several relevant barriers and high potential of the planned decision framework tool to overcome this.
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