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Emptying the stores: lysosomal diseases and therapeutic strategies

Nature Reviews Drug Discovery volume 17, pages 133–150 (2018)Cite this article

Subjects

Key Points

  • Lysosomal storage disorders (LSDs) include over 70 inborn errors of metabolism that collectively affect 1 in 5,000 live births but individually are orphan diseases.

  • How the primary defect, usually in a lysosomal enzyme, leads to a complex pathogenic cascade and typically neurodegeneration is incompletely understood.

  • Some LSDs can be prevented by carrier screening of at-risk populations, but currently, most countries do not include these diseases on newborn screening panels, primarily because most are without effective treatment.

  • Several therapies have been developed for specific LSDs and include enzyme replacement therapy, substrate reduction therapy and chemical chaperone therapy with haematopoietic stem cell transplantation.

  • Experimental therapies at the stage of clinical trials include gene therapy, heat shock protein 70 (HSP70)-inducing chaperone therapy and other disease-specific therapies.

  • Currently, there is a great deal of commercial activity in this field, catalysed by the incentives arising from orphan drug legislation.

Abstract

Lysosomal storage disorders (LSDs) — designated as 'orphan' diseases — are inborn errors of metabolism caused by defects in genes that encode proteins involved in various aspects of lysosomal homeostasis. For many years, LSDs were viewed as unattractive targets for the development of therapies owing to their low prevalence. However, the development and success of the first commercial biologic therapy for an LSD — enzyme replacement therapy for type 1 Gaucher disease — coupled with regulatory incentives rapidly catalysed commercial interest in therapeutically targeting LSDs. Despite ongoing challenges, various therapeutic strategies for LSDs now exist, with many agents approved, undergoing clinical trials or in preclinical development.

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Figure 1: The complexity of practical and ethical issues raised by newborn screening.
Figure 2: The pathogenic cascade in lysosomal storage disorders (LSDs).
Figure 3: The major sites of action of the current lysosomal storage disorder therapeutics.

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Acknowledgements

The author would like to thank B. Owen (Niemann–Pick UK) for helpful discussions on prevention, M. Hughes and A. Rahim for the current status of gene therapy trials, B. Winchester for comparing notes on the current status of enzyme replacement therapy trials and N. Platt and D. Priestman for comments on the manuscript. F.P. is a Wellcome Investigator in Science and a Royal Society Wolfson Merit Award Holder.

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    Frances M. Platt

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F.P. is a consultant to Actelion, E3Bio and Orphazyme and a co-founder and consultant to IntraBio.

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Glossary

Lysosomal storage disorders

(LSDs). Disorders in which macromolecules build up in lysosomes, leading to so-called 'storage' as a result of an inherited mutation in a gene involved in lysosomal function.

Multimorbidity

Individuals with multiple, typically chronic, clinical conditions.

Biologic therapies

Treatments derived from living organisms to treat a disease. In the field of lysosomal storage disorders, enzyme replacement therapy, cell transplantation and gene therapy are all biologic therapies.

Lysosome

An acidic organelle involved in macromolecule catabolism and recycling but also plays a role in nutrient sensing and calcium signalling.

Proteostasis

The integrated process of protein synthesis, folding, trafficking and catabolism. Modulating this process is a therapeutic strategy for treating protein-misfolding diseases, including lysosomal storage disorders.

Proteostasis modifiers

Drugs that increase the activity of the protein-folding machinery of the cell to aid folding of misfolded mutant proteins.

Chemical chaperones

Drugs that either bind the active site of a mutant enzyme and stabilize it or are allosteric binders, binding away from the active site but still stabilizing the protein.

Substrate reduction therapy

(SRT). A small-molecule drug that inhibits the biosynthesis of substrates that are stored in a lysosomal storage disorder.

Polypharmacology

Treating a disease using a combination of therapies to maximize clinical benefit.

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Platt, F. Emptying the stores: lysosomal diseases and therapeutic strategies. Nat Rev Drug Discov 17, 133–150 (2018). https://doi.org/10.1038/nrd.2017.214

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