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Enzyme replacement and enhancement therapies: lessons from lysosomal disorders

Nature Reviews Genetics volume 3, pages 954–966 (2002)Cite this article

A Correction to this article was published on 01 February 2003

Key Points

  • Lysosomal storage diseases (LSDs) are caused by mutations in genes that encode lysosomal proteins, in most cases lysosomal enzymes.

  • Most treatment strategies for LSDs are based on replacing the missing or defective lysosomal protein in the appropriate target sites of pathology.

  • In the 1990s, several 'breakthrough' technologies led to the rapid development of enzyme replacement therapy (ERT) for LSDs. These included: the development of eukaryotic expression systems for lysosomal proteins; and the construction of new mouse models of LSDs by gene targeting.

  • Preclinical studies in animal models have shown the efficacy of ERT for the treatment of LSDs, but have also identified its limitations, including the inability to deliver exogenous enzymes efficiently to the central nervous system (CNS).

  • ERT became available for the first LSD — type I Gaucher disease — in 1991, and ten years of experience in more than 3,000 patients has revealed its remarkable efficacy and safety.

  • ERT is also available for Fabry disease, and is now being evaluated in clinical trials for several other LSDs.

  • New therapeutic strategies, including chaperone-mediated enzyme enhancement therapy (EET), are now being evaluated for LSDs.

  • One principal advantage of EET as compared with ERT is the potential for treating diseases with CNS involvement, because low-molecularweight pharmacological chaperones are able to cross the blood–brain barrier.

Abstract

The past decade has witnessed remarkable advances in our ability to treat inherited metabolic disorders, especially the lysosomal storage diseases, a group of more than 40 disorders, each of which is caused by the deficiency of a lysosomal enzyme or protein. During the past few years, both enzyme replacement and enhancement therapies have been developed to treat these disorders. This review discusses the successes and shortcomings of these therapeutic strategies, and the contributions that they have made to treating lysosomal storage diseases.

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Figure 1: Lysosomal enzyme sorting by the mannose-6-phosphate receptor system.
Figure 2: Proposed mechanism of enzyme rescue by pharmacological chaperones.

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Acknowledgements

The authors thank K. H. Astrin for his assistance with the manuscript. The authors are funded by grants from the National Institutes of Health and a basic research grant from Genzyme Corporation. R.J.D. is a consultant for the Genzyme Corporation and Amicus Therapeutics. E.H.S. is a consultant for the Genzyme Corporation.

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Authors and Affiliations

  1. Department of Human Genetics, Mount Sinai School of Medicine at New York University, New York, 10029, New York, USA

    Robert J. Desnick & Edward H. Schuchman

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  1. Robert J. Desnick
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  2. Edward H. Schuchman
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Correspondence to Robert J. Desnick.

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DATABASES

LocusLink

ABCB1

CFTR

α-Gal A

GLA

OMIM

Alzheimer disease

cystic fibrosis

Fabry disease

galactosialidosis

Metachromatic leukodystrophy

Mucopolysaccharidosis type I

Mucopolysaccharidosis type II

Mucopolysaccharidosis type IIIA

Mucopolysaccharidosis type IIIB

Mucopolysaccharidosis type VI

Mucopolysaccharidosis type VII

Pompe disease

Sandhoff disease

Tay–Sachs disease

type I Gaucher disease

type II Gaucher disease

type III Gaucher disease

Type A/B Niemann–Pick

Wolman disease

FURTHER INFORMATION

Biomarin, Inc

European Agency for Evaluation of Medical Products

Genzyme Corporation

March of Dimes Birth Defects Foundation

Transkaryotic Therapies

United States Food and Drug Administration

Glossary

SPHINGOLIPID

A lipid that contains a sphingosine backbone. Fatty acids are often attached to the nitrogen atom of the sphingosine moiety, generating N-acylsphingosines (ceramides).

MUCOPOLYSACCHARIDES

A group of polysaccharides that have characteristic repeating disaccharide units, each consisting of an N-acetylated hexosamine residue and a uronic-acid residue.

GLYCOPROTEIN

Any one of a class of conjugated proteins that consist of a polypeptide backbone linked to a carbohydrate group.

ENDOCYTOSIS

The uptake of extracellular materials by cells. The plasma membrane invaginates and vesicles pinch off that contain endocytosed molecules and plasma membrane components.

PHAGOCYTOSIS

A process by which cells engulf external soluble and particulate material.

CATABOLISM

A metabolic process by which organisms convert substances into simpler molecules.

PANCYTOPAENIA

A deficiency of all types of blood cell.

HEPATOSPLENOMEGALY

Abnormal enlargement of the spleen and liver.

NON-NEUTRALIZING ANTIBODY

Antibodies that do not inactivate the function of a protein.

SEROCONVERT

The changing of a serological test from negative to positive, indicating the development of antibodies in response to infection or immunization.

ORPHAN DRUG

A drug that is used to treat patients with a rare (or 'orphan') disease.

GLYCOSPHINGOLIPID

A sphingolipid that contains sugars. Common classes of these lipids include cerebrosides and gangliosides.

PROTEASOME

The protein complex that is responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

NONSENSE MUTATION

A mutation that results in the introduction of a stop codon to cause the premature termination of the protein.

NONSENSE-MEDIATED MRNA DECAY

(NMD). A pathway ensuring that mRNAs that bear premature stop codons are eliminated as templates for translation.

ACTIVE SITE

The part of an enzyme that is responsible for its catalytic function.

α1-ANTITRYPSIN

A serine protease inhibitor that is produced in the liver and secreted into the plasma, which inhibits the activity of trypsin and elastase. α1-Antitrypsin deficiency is associated with emphysema and liver disease.

OSMOLYTE

A molecule that can alter the ionic concentration of a solution.

P-GLYCOPROTEIN

A protein that is responsible for multiple drug resistance.

GOLGI APPARATUS

A lamellar membranous structure, near the nucleus of most cells, that is the site of protein modification (such as N-glycosylation) and sorting.

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Desnick, R., Schuchman, E. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nat Rev Genet 3, 954–966 (2002). https://doi.org/10.1038/nrg963

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