Emptying the Stores: Lysosomal Diseases and Therapeutic Strategies

Overview

Journal Nat Rev Drug Discov

Specialty Pharmacology

Date 2017 Nov 18

PMID 29147032

Citations 122

Authors

Frances M Platt

Affiliations

Soon will be listed here.

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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References

Lachmann R . Enzyme replacement therapy for lysosomal storage diseases. Curr Opin Pediatr. 2011; 23(6):588-93. DOI: 10.1097/MOP.0b013e32834c20d9. View

Desnick R, Schuchman E . Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet. 2012; 13:307-35. DOI: 10.1146/annurev-genom-090711-163739. View

Kornfeld S . Trafficking of lysosomal enzymes. FASEB J. 1987; 1(6):462-8. DOI: 10.1096/fasebj.1.6.3315809. View

Aerts J, Hollak C, van Breemen M, Maas M, Groener J, Boot R . Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases. Acta Paediatr Suppl. 2005; 94(447):43-6. DOI: 10.1111/j.1651-2227.2005.tb02110.x. View

Walkley S . Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol. 2004; 15(4):433-44. DOI: 10.1016/j.semcdb.2004.03.002. View

Kirkegaard T, Gray J, Priestman D, Wallom K, Atkins J, Olsen O . Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med. 2016; 8(355):355ra118. PMC: 6821533. DOI: 10.1126/scitranslmed.aad9823. View

Lew R, Burnett L, Proos A, Barlow-Stewart K, Delatycki M, Bankier A . Ashkenazi Jewish population screening for Tay-Sachs disease: the international and Australian experience. J Paediatr Child Health. 2014; 51(3):271-9. DOI: 10.1111/jpc.12632. View

Wasserstein M, Andriola M, Arnold G, Aron A, Duffner P, Erbe R . Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016; 18(12):1235-1243. DOI: 10.1038/gim.2016.35. View

Kalmar B, Greensmith L . Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects. Cell Mol Biol Lett. 2009; 14(2):319-35. PMC: 6275696. DOI: 10.2478/s11658-009-0002-8. View

10.

Deane C, Brown I . Induction of heat shock proteins in differentiated human neuronal cells following co-application of celastrol and arimoclomol. Cell Stress Chaperones. 2016; 21(5):837-48. PMC: 5003800. DOI: 10.1007/s12192-016-0708-2. View

11.

Brady R . Enzyme replacement therapy: conception, chaos and culmination. Philos Trans R Soc Lond B Biol Sci. 2003; 358(1433):915-9. PMC: 1693186. DOI: 10.1098/rstb.2003.1269. View

12.

Narita A, Shirai K, Itamura S, Matsuda A, Ishihara A, Matsushita K . Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study. Ann Clin Transl Neurol. 2016; 3(3):200-15. PMC: 4774255. DOI: 10.1002/acn3.292. View

13.

Biegstraaten M, Cox T, Belmatoug N, Berger M, Collin-Histed T, Vom Dahl S . Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease. Blood Cells Mol Dis. 2017; 68:203-208. DOI: 10.1016/j.bcmd.2016.10.008. View

14.

Wassif C, Cross J, Iben J, Sanchez-Pulido L, Cougnoux A, Platt F . High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet Med. 2015; 18(1):41-8. PMC: 4486368. DOI: 10.1038/gim.2015.25. View

15.

Foust K, Nurre E, Montgomery C, Hernandez A, Chan C, Kaspar B . Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2008; 27(1):59-65. PMC: 2895694. DOI: 10.1038/nbt.1515. View

16.

Barnett K, Mercer S, Norbury M, Watt G, Wyke S, Guthrie B . Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012; 380(9836):37-43. DOI: 10.1016/S0140-6736(12)60240-2. View

17.

Thurberg B, Wasserstein M, Jones S, Schiano T, Cox G, Puga A . Clearance of Hepatic Sphingomyelin by Olipudase Alfa Is Associated With Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency. Am J Surg Pathol. 2016; 40(9):1232-42. PMC: 4987207. DOI: 10.1097/PAS.0000000000000659. View

18.

Prakash V, Moore M, Yanez-Munoz R . Current Progress in Therapeutic Gene Editing for Monogenic Diseases. Mol Ther. 2016; 24(3):465-74. PMC: 4786935. DOI: 10.1038/mt.2016.5. View

19.

Marshall J, Sun Y, Bangari D, Budman E, Park H, Nietupski J . CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease. Mol Ther. 2016; 24(6):1019-1029. PMC: 4923322. DOI: 10.1038/mt.2016.53. View

20.

Galli R, Gritti A, Bonfanti L, Vescovi A . Neural stem cells: an overview. Circ Res. 2003; 92(6):598-608. DOI: 10.1161/01.RES.0000065580.02404.F4. View