In 1966, evidence of a marked reduction in glucocerebrosidase enzyme activity was reported in the spleen of patients with Gaucher disease.1 This led to the concept that enzyme replacement therapy could be a therapeutic strategy for patients, and its clinical effectiveness was tested in the 1990s in patients with Gaucher disease.2 The introduction of enzyme replacement therapy and substrate reduction therapy has enhanced the management of Gaucher disease.3,4 However, it should be noted that Gaucher disease-specific therapies are only effective for the treatment of visceral manifestations, as they do not affect the neurological symptoms of Gaucher disease.4
In addition to pharmacological treatment for Gaucher disease, complementary therapies such as physical therapy or orthopaedic measures to restore bone complications associated with the disease may be used.5 Clinicians should encourage self-management education to help patients understand their disease and treatment options, cope with symptoms, manage medications, and communicate with clinicians.6
Due to the heterogeneous nature of the disease, the management of Gaucher disease requires a patient-centric approach, and recommendations are available for:
Three intravenous enzyme replacement therapies and two oral substrate reduction therapies are available for patients with Gaucher disease. The principle of enzyme replacement therapy is to supply cells, particularly Gaucher cells, with glucocerebrosidase due to reduced enzyme activity.12 Substrate reduction therapies for Gaucher disease reduce synthesis of glucosylceramide, which is a substrate of glucocerebrosidase, and builds up in the cell due to reduced enzymatic activity of glucocerebrosidase (Figure 1).12
The availability of these treatments differs between countries. For further information, please consult your local prescribing information.
In patients with Gaucher disease, enzyme replacement therapy restores the breakdown of glucosylceramide, whereas substrate reduction therapy reduces the production of glucosylceramide12
What future treatments could be available for Gaucher disease?
New treatment modalities are currently being researched for Gaucher disease. The feasibility of gene therapy for Gaucher disease was initially investigated in a retroviral vector, where the human GBA1 gene was transduced into fibroblasts and haematopoietic progenitor cells derived from patients with Gaucher disease, to normalise activity of GBA1.13,14 Since this study, the field of gene therapy has advanced, with evidence of self-inactivating lentiviral vectors with GBA1 preventing and reversing disease manifestations in a conditional knockout mouse model of Gaucher disease.15 Lentiviral vector gene therapy for patients with Gaucher disease Type 1 have now entered early-phase clinical trials.16
Small molecules designed to bind specific target proteins and assist in protein folding, termed ‘pharmacological chaperones’, are being developed as an alternative treatment approach for Gaucher disease and Gaucher disease-related Parkinson’s disease.17 Since current treatments for neuronopathic Gaucher disease do not affect neurological manifestations, pharmacological chaperones that cross the blood–brain barrier may provide a therapeutic strategy to target the neurological involvement associated with Gaucher disease, and its link to Parkinson’s disease.4,17 Another treatment approach may be the use of non-inhibitory chaperones. These are small molecules that aid folding of the mutant enzyme in the endoplasmic reticulum and help translocate the enzyme to lysosomes. The principle behind non-inhibitory chaperones in Gaucher disease is that they would restore residual glucocerebrosidase functioning within lysosomes.14,18
C-ANPROM/INT//7568; Date of preparation: September 2020
- Brady RO, Kanfer JN, Bradley RM, et al. Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease. J Clin Invest 1966; 45: 1112-1115.
- Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991; 324: 1464-1470.
- Revel-Vilk S, Szer J, Mehta A, et al. How we manage Gaucher disease in the era of choices. Br J Haematol 2018; 182: 467-480.
- Roshan Lal T, Sidransky E. The spectrum of neurological manifestations associated with Gaucher disease. Diseases (Basel, Switzerland) 2017; 5: 10.
- German Society for Child and Youth Medicine Working Group on Pediatric Metabolic Disorders. Gaucher's disease guidelines. March 2006. Available at https://www.ggd-ev.de/wp-content/uploads/mgaucher-22-12-2007.pdf. Accessed September 2020.
- Haute Autorité de Santé. Gaucher disease: national diagnosis and treatment protocol. January 2007. Available at https://www.has-sante.fr/upload/docs/application/pdf/ven_gaucher_web.pdf. Accessed September 2020.
- Biegstraaten M, Cox TM, Belmatoug N, et al. Management goals for Type 1 Gaucher disease: an expert consensus document from the European Working Group on Gaucher disease. Blood Cells Mol Dis 2018; 68: 203-208.
- Weiss K, Gonzalez A, Lopez G, et al. The clinical management of Type 2 Gaucher disease. Mol Genet Metab 2015; 114: 110-122.
- The Belgian Working Group on Gaucher disease. Guidelines for diagnosis, treatment and monitoring of Gaucher's disease. May 2016. Available at https://cema.uza.be/static/documenten/informatie_metabole_ziekten/Belgian%20Expert%20Opinion%20for%20Diagnosis,%20Treatment%20an%20Monitoring%20of%20Gaucher.pdf. Accessed September 2020.
- Granovsky-Grisaru S, Belmatoug N, vom Dahl S, et al. The management of pregnancy in Gaucher disease. Eur J Obstet Gynecol Reprod Biol 2011; 156: 3-8.
- Futerman AH, Zimran A. Gaucher disease. Boca Raton, FL; Taylor & Francis, 2007.
- Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017; 18: 441.
- Fink JK, Correll PH, Perry LK, et al. Correction of glucocerebrosidase deficiency after retroviral-mediated gene transfer into hematopoietic progenitor cells from patients with Gaucher disease. Proc Natl Acad Sci U S A 1990; 87: 2334-2338.
- Mistry PK, Lopez G, Schiffmann R, et al. Gaucher disease: progress and ongoing challenges. Mol Genet Metab 2017; 120: 8-21.
- Dahl M, Doyle A, Olsson K, et al. Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice. Mol Ther 2015; 23: 835-844.
- ClinicalTrials.gov. Phase 1/2 lentiviral vector gene therapy - The GuardOne Trial of AVR-RD-02 for subjects with Type 1 Gaucher disease. Available at: https://clinicaltrials.gov/ct2/show/NCT04145037?term=NCT04145037&draw=2&rank=1. Accessed September 2020.
- Han TU, Sam R, Sidransky E. Small molecule chaperones for the treatment of Gaucher disease and GBA1-associated Parkinson disease. Front Cell Dev Biol 2020; 8: 271.
- Jung O, Patnaik S, Marugan J, et al. Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease. Expert Rev Proteomics 2016; 13: 471-479.