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Review
. 2021 Jan;44(1):129-147.
doi: 10.1002/jimd.12316. Epub 2020 Sep 28.

Novel therapies for mucopolysaccharidosis type III

Berna Seker Yilmaz  1   2 , James Davison  3 , Simon A Jones  4 , Julien Baruteau  1   3   5
Affiliations
Review

Novel therapies for mucopolysaccharidosis type III

Berna Seker Yilmaz et al. J Inherit Metab Dis. 2021 Jan.

Abstract

Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile-onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease-modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno-associated or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first-in-man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease-modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.

Keywords: Sanfilippo disease; adeno-associated virus; enzyme replacement therapy; gene editing; gene therapy; heparan sulfate; lentivirus; lysosomal storage disease; mRNA; mucopolysaccharidosis type III; substrate reduction therapy.

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Conflict of interest statement

B. S. Y. and J. B. have no conflict of interest. S. A. J. is an investigator and consultant for Shire/Takeda; consultant for Biomarin; investigator and consultant for Alexion; investigator, consultant, SAB member and Stockholder for Orchard. J. D. is an investigator for Sanofi Genzyme; consultant for Biomarin and Sanofi Genzyme; received educational grants from Shire and Biomarin.

Figures

FIGURE 1
FIGURE 1
Neurovisceral disease in mucopolysaccharidosis type III. This schematic representation of the classical form of the disease show the main symptoms with age of onset
FIGURE 2
FIGURE 2
Degradation of the glycosaminoglycan chain heparan sulfate. The deficient enzymes involved in the different subtypes of MPS type III are highlighted. MPS III, mucopolysaccharidosis type III; NAc, N‐acetyl; SO3−, sulfate
FIGURE 3
FIGURE 3
General principles and main routes of administration of enzyme replacement and adeno‐associated viral (AAV) and lentiviral vectors mediated gene therapy. HSC, haematopoietic stem cell
See this image and copyright information in PMC

References

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