Pharmacotherapy of Gaucher Disease: Current and Future Options

Lunawati L Bennett, Chris Fellner, Lunawati L Bennett, Chris Fellner

Abstract

The clinical manifestations of Gaucher disease, a rare genetic lysosomal storage disorder, are debilitating, and the neuronopathic forms of the disease are fatal. The authors describe the current and investigational therapies for treatment.

Conflict of interest statement

Disclosures: The authors report no commercial or financial interests in regard to this article.

References

    1. Grabowski G. Gaucher disease: enzymology, genetics, and treatment. In: Harris H, Hirshchorn K, editors. Advances in Human Genetics. Vol. 21. New York, New York: Plenum Press; 1993. pp. 377–441.
    1. Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation, and treatments. Int J Mol Sci. 2017;18(2):E441.
    1. Goker-Alpan O. Therapeutic approaches to bone pathology in Gaucher disease: past, present, and future. Mol Genet Metab. 2011;104:438–447.
    1. Conradi NG, Kalimo H, Sourander P. Reactions of vessel walls and brain parenchyma to the accumulation of Gaucher cells in the Norrbottnian type (type III) of Gaucher disease. Acta Neuropathol. 1988;75:385–390.
    1. Grabowski GA. Gaucher disease and other storage disorders. Hematology Am Soc Hematol Educ Program. 2012;2012:13–18.
    1. Genes and Disease. Bethesda, Maryland: National Center for Biotechnology Information; 1998. [Accessed September 12, 2014]. Gaucher disease. Available at: .
    1. Pastores GM, Hughes DA. Gaucher disease. [Accessed June 8, 2012]. Available at: .
    1. Beutler E, Grabowski GA. Gaucher disease. In: Scriver C, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Basis of Inherited Diseases. 8th ed. New York, New York: McGraw-Hill; 2001. pp. 3635–3668.
    1. Hruska KS, LaMarca ME, Scott CR, et al. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA) Hum Mutat. 2008;29:567–583.
    1. Butters TD, Mellor HR, Nariya K, et al. Small-molecule therapeutics for the treatment of glycolipid lysosomal storage disorders. Phil Trans R Soc Lond B Biol Sci. 2003;358:927–945.
    1. Zimran A, Gelbart T, Westwood B, et al. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991;49:855–889.
    1. Zimran A, Elstein D. Lipid storage diseases. In: Lichtman MA, Kipps T, Seligsohn U, et al., editors. Williams Hematology. 8th ed. New York, New York: McGraw-Hill; 2010. pp. 1065–1071.
    1. Benito JM, Fernandez JMG, Mellet CO. Pharmacological chaperone therapy for Gaucher disease: a patent review. Expert Op Ther Patents. 2011;21:885–903.
    1. Bohlega S, Kambouris M, Shahid M, et al. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIc) Neurology. 2000;54:261–263.
    1. Jeong SY, Park SJ, Kim HJ. Clinical and genetic characteristics of Korean patients with Gaucher disease. Blood Cells Mol Dis. 2011;46:11–14.
    1. 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.
    1. Mankin HJ, Rosenthal DI, Xavier R. Gaucher disease: new approaches to an ancient disease. J Bone Joint Surg. 2001;83:748–762.
    1. 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.
    1. Weinreb NJ, Charrow J, Andersson HC, et al. Effectiveness of enzyme replacement therapy in 1,028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002;11:112–119.
    1. Desnick RJ, Schuchman EH. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nat Rev Genet. 2002;3:954–966.
    1. Grabowski GA, Barton NW, Pastores G, et al. Enzyme therapy in Gaucher disease type 1: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Int Med. 1995;122:33–39.
    1. Jmoudiak M, Futerman AH. Gaucher disease: pathological mechanisms and modern management. Br J Hematol. 2005;129:178–188.
    1. Hollak CE, vom Dahl S, Aerts JM, et al. Force majeure: therapeutic measures in response to restricted supply of imglucerase (Cerezyme) for patients with Gaucher disease. Blood Cells Mol Dis. 2010;44:41–47.
    1. Burrow T, Grabowski GA. Velaglucerase alfa in the treatment of Gaucher disease type 1. Clin Investig (Lond) 2011;1:285–293.
    1. Pfizer. Pfizer and Protalix BioTherapeutics announce FDA approval of Elelyso (taliglucerase alfa) for the treatment of Gaucher disease. May 1, 2012. [Accessed January 24, 2018]. Available at: .
    1. Zimran A, Brill-Almon E, Chertkoff R, et al. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood. 2011;118:5767–5773.
    1. Tekoah Y, Tzaban S, Kizhner T, et al. Glycosylation and functionality of recombinant β-glucocerebrosidase from various production systems. Biosci Rep. 2013;33:e00071.
    1. Dwek RA, Butters TD, Platt FM, et al. Targeting glycosylation as a therapeutic approach. Nat Rev Drug Discov. 2002;1:65–75.
    1. van Patten SM, Hughes H, Huff MR, et al. Effect of mannose chain length on targeting glucocerebrosidase enzyme replacement therapy of Gaucher disease. Glycobiology. 2007;17:467–478.
    1. Vpriv (velaglucerase alfa for injection) prescribing information. Lexington, Massachusetts: Shire Human Genetic Therapies, Inc.; 2015.
    1. Red Book Online. Ann Arbor, Michigan: Truven Health Analytics; [Accessed January 24, 2018].
    1. Shayman JA. In memoriam: Norman S. Radin (1920–2013) J Lipid Res. 2013;54:1713–1715.
    1. DailyMed Zavesca–miglustat capsule. National Library of Medicine; Nov 16, 2017. [Accessed January 24, 2018]. Available at: .
    1. Cerdelga (eliglustat) prescribing information. Waterford, Ireland: Genzyme; 2014.
    1. McWachern KA, Fung J, Komarnitsky S, et al. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab. 2007;91:259–267.
    1. Schiffmann R, Fitzgibbon EJ, Harris C, et al. Randomized controlled trial of miglustat in Gaucher’s disease type 3. Ann Neurol. 2008;64:514–522.
    1. Belmatoug N, Burlina A, Giraldo P, et al. Gastrointestinal disturbances and their management in milglustat-treated patients. J Inherit Metab Dis. 2011;34:991–1001.
    1. Lukina E, Watman N, Dragosky M, et al. Eliglustat, an investigational oral therapy for Gaucher disease type 1: phase 2 trial results after 4 years of treatment. Blood Cell Mol Dis. 2014;53:274–276.
    1. Kamath RS, Lukina E, Watman N, et al. Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat. Skeletal Radiol. 2014;43:1353–1360.
    1. Mistry PK, Lukina E, Ben Turkia H, et al. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA. 2015;313:695–706.
    1. Cox TM, Drelichman G, Cravo R, et al. Eliglustat compared with imiglucerase in patients with Gaucher’s disease type 1 stabilized on enzyme replacement therapy: a phase 3, randomized, open-label non-inferiority trial. Lancet. 2015;385(9985):2355–2362.
    1. . A study of eliglustat tartrate (Genz-112638) in patients with Gaucher disease (ENGAGE). NCT00891202. Mar 3, 2017. [Accessed January 24, 2018]. Available at: .
    1. Shayman JA. Eliglustat tartrate: glucosylceramide synthase inhibitor treatment of type 1 Gaucher disease. Drugs Fut. 2010;35(8):613–620.
    1. Shayman JA. The design and clinical development of inhibitors of glycosphingolipids synthesis: will invention be the mother necessity? Trans Am Clin Climatol Assoc. 2013;124:46–60.
    1. Cox TM, Drelichman G, Cravo R, et al. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood. 2017;129:2375–2383.
    1. Misty PK, Lukina E, Ben Turkia H, et al. Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial. Am J Hematol. 2017;92(11):1170–1176.
    1. El-Beshlawy A, Tylki-Szymanska A, Vellodi A, et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. Mol Gene Metab. 2017;120:47–56.
    1. Brady RO. Benefits from unearthing “a biochemical Rosetta Stone”. J Biol Chem. 2010;285(53):41216–41221.
    1. Sechi A, Deroma A, Dardis G, et al. Long-term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients. Mol Genet Metab. 2014;113(3):213–218.
    1. Erdemir G, Ozkan T, Ozgur T, et al. Pediatric Gaucher experience in South Marmara region of Turkey. Turk J Gastroenterol. 2011;22(5):500–504.
    1. Kraoua I, Sedel F, Caillaud C, et al. A French experience of type 3 Gaucher disease: phenotyping diversity and neurological outcome of 10 patients. Brain Dev. 2011;33(2):131–139.
    1. Tylki-Szymanska A, Vellodi A, El-Beshlawy A, et al. Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. J Inherit Metab Dis. 2010;33:339–346.
    1. Erikson A. Gaucher disease-Norrbottnian type (III). Neuropediatric and neurobiological aspects of clinical patterns and treatment. Acta Paediatr Scand Suppl. 1986;326:1–42.
    1. Rastogi P, Rao S, Kaur J, et al. Gaucher’s disease with cardiac valve calcification and stenosis: a rare presentation due to homozygous pD409H mutation in a north Indian family. Indian J Pediatr. 2016;83(8):877–878.
    1. Ceravolo F, Grisolia M, Sestito S, et al. Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report. J Med Case Rep. 2017;11(1):19.
    1. Capablo JL, Franco R, deCabezon AS, et al. Neurological improvement in a type 3 Gaucher disease patient treated with imiglucerase/miglustat combination. Epilepsia. 2007;48:1406–1408.
    1. Goker-Alpan O, Wiggs EA, Eblan MJ, et al. Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease. J Pediatr. 2008;153:89–94.
    1. Shah S, Misri A, Bhat S, et al. Gaucher’s disease type III C: unusual cause of intracardiac calcification. Ann Pediatr Cardiol. 2008;1:144–146.
    1. Cox-Brinkman J, Van Breemen MJ, van Maldegem BT, et al. Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III. J Inherit Metab Dis. 2008;31:745–752.
    1. . Search results: Gaucher disease 3. [Accessed January 24, 2018]. Available at: .
    1. Rappeport JM, Ginns EI. Bone-marrow transplantation in severe Gaucher’s disease. N Engl J Med. 1984;311:84–88.
    1. Tsai P, Lipton JM, Sahdev I, et al. Allogenic bone marrow transplantation in severe Gaucher disease. Pediatr Res. 1992;31:503–507.
    1. Children’s Gaucher Research Fund. GD2/3 in depth. [Accessed January 24, 2018]. Available at: .
    1. Baek RC, Kasperzyk JL, Platt FM, et al. N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice. Neurochem Int. 2008;16(3):1125–1133.
    1. Guerard N, Morand O, Dingemanse J. Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects. Orphanet J Rare Dis. 2017;12(1):9.
    1. Butters TD, van den Broek LAGM, Fleet GWJ, et al. Molecular requirements of imino sugars for the selective control of N-linked glycosylation and glycosphingolipid biosynthesis. Tetrahedron Asymmetry. 2000;11(1):113–124.
    1. Ridley CM, Thur KE, Shanahan J, et al. Beta glucosidase 2 (GBA2) activity and imino sugar pharmacology. J Biol Chem. 2013;288(36):26052–26066.
    1. Pawlinski L, Malecki MT, Kiec-Wilk B. The additive effect on the antiepileptic treatment of ambroxol in type 3 Gaucher patient. The early observation. Blood Cells Mol Dis. 2018;68:192–193.
    1. Maegawa GH, Tropak MB, Buttner JD, et al. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem. 2009;284:23502–23516.
    1. Babajani G, Tropak MB, Mahran DJ, et al. Pharmacological chaperone facilitate the post-ER transport of recombinant N370S mutant β-glucocerebrosidase in plant cells; evidence that N370 is a folding mutant. Mol Genet Metab. 2012;106:323–329.
    1. Narita A, Shirai K, Itamura S, et al. Ambroxol chaperone therapy for neuronopathic Gaucher disease: a pilot study. Ann Clin Transl Neurol. 2016;3(3):200–215.
    1. Sun Y, Liou B, Xu YH, et al. Gaucher disease: ex vivo and in vivo effects of isofagomine on acid beta-glucosidase variants and substrate levels. J Biol Chem. 2011;287:4275–4287.
    1. Amicus Therapeutics. Amicus Therapeutics announces preliminary results of phase 2 study with Plicera for Gaucher disease. Oct 2, 2009. [Accessed October 6, 2015]. Available at: .
    1. Yang C, Rahimpour S, Lu J, et al. Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones. Proc Natl Acad Sci U S A. 2013;110:966–971.
    1. Lu J, Yang C, Chen M, et al. Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease. Proc Natl Acad Sci U S A. 2011;18:21200–21205.
    1. Johnstone RW. Histone-deacetylase (HDAC) inhibitors: Novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1(4):287–299.
    1. Faraco G, Pittelli M, Cavone L, et al. Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Dis. 2009;36(92):269–279.
    1. Thomas EA. Focal nature of neurological disorders necessitates isotype-selective histone deacetylase inhibitors. Mol Neurobiol. 2009;40(1):33–45.
    1. Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann Pharmacother. 2013;47(9):1182–1193.
    1. Bennett LL, Turcotte K. Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease. Drug Design Devel Therapy. 2015;9:4639–4647.
    1. Pastores GM, Weinreb NJ, Aerts H. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41:4–14.

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