Sanfilippo type C disease: pathogenic mechanism and potential therapeutic applications

ABSTRACT

Introduction: A rare orphan disorder, Mucopolysaccharidosis III type C (MPS IIIC) is caused by mutations in the HGSNAT (heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase) gene resulting in lysosomal storage of heparan sulfate (HS). In the brain, HS accumulation triggers neuronal death leading to neuropsychiatric problems, mental retardation, and dementia.

Areas covered: The review describes the discovery of lysosomal transmembrane acetylation and its deficiency in MPS IIIC, identification of the causative gene and mutations in the patients and the analysis of pathophysiological mechanism in the mouse models of the disease. These studies have shown that storage of HS in the microglial cells and their activation triggers neuroinflammation and neuronal death. Many MPS IIIC patients have missense mutations resulting in the synthesis of misfolded protein and partially amendable by pharmacological chaperons. In the mouse model disease can be prevented by supraphysiological delivery of wild-type HGSNAT via AAV-mediated gene transfer.

Expert opinion: The recent advances in understanding the disease pathology and preclinical research suggest that treatment for MPS IIIC can be developed by using two orthogonal strategies: (1) gene/cell therapy and (2) chaperone therapy to restore folding of HGSNAT missense mutants. Importantly, both approaches could be used together to increase the probability of success.

KEYWORDS:

• Mucopolysaccharidosis
• Sanfilippo disease
• heparan sulfate
• neurodegeneration
• AAV
• chaperone therapy
• neuroinflammation

Article highlights

• Discovery of the underlying biochemical and molecular mechanism of MPS IIIC

• HGSNAT mutation spectrum

• Misfolded HGSNAT mutants with amino acid substitutions and chaperone therapy for MPS IIIC

• Mouse models of MPS IIIC and pathophysiology of neurological symptoms

• Experimental and preclinical therapies in MPS IIIC

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Declaration of interest

A Pshezhetsky is a shareholder of Phoenix Nest Inc. that holds a licence for using AAV-TT for the therapy of MPS IIIC; receives travel grants and honoraria from Phoenix Nest Inc., Sanofi-Genzyme Inc., and Bio-Marine. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This article has been partially supported by an operating grant PJT 156345 from the Canadian Institutes of Health Research, an operating grant from Sanfilippo Children's Foundation and a gift from Sanfilippo Children’s Research Foundation to A. Pshezhetsky.