Pharmacotherapeutic strategies using small molecules for the treatment of glycolipid lysosomal storage disorders

Abstract

The glycolipid lysosomal storage diseases are a collection of rare, inherited disorders of metabolism associated with heterogeneous pathologies and reduced life expectancy. Reduction of the substrate that accumulates due to catabolic enzyme deficiency can be mediated by an increasing number of therapeutic approaches, including enzyme replacement, pharmacological intervention to reduce substrate synthesis or enhance residual enzyme activity, and cell or gene therapy. The success of one agent, the imino sugar miglustat, has provided the impetus for using similar molecules for enzyme enhancement, or chaperone-mediated therapy for exiting medical conditions and for conditions where no disease-specific therapy is available. The advantages of using small molecules as therapy for the family of lysosomal storage disorders are discussed with reference to existing enzyme replacement therapies.

Keywords::

• chaperones
• Gaucher disease
• imino sugar inhibitors
• substrate reduction therapy

Acknowledgements

The author thanks the Oxford Glycobiology Institute for support and Actelion for providing the current IS3 data.

Disclosure

The author’s laboratory was provided with a grant (June 2000 – June 2006) following the discovery of miglustat for SRT, to generate data sufficient for clinical trial approval. This support (only partial for the entire University-led laboratory) was provided by Oxford GlycoSciences, who were eventually acquired by Celltech. Miglustat is now marketed exclusively by Actelion and the author is not in receipt of grants, support or consultancies from neither Celltech nor Actelion.

The author is in receipt of a 6-month pilot study grant provided by Amicus, to study the effects on protein folding pathways during lysosomal storage.