Optimal therapy in Gaucher disease

Ozlem Goker-Alpan, Ozlem Goker-Alpan

Abstract

Gaucher disease (GD), the inherited deficiency of the lysosomal enzyme glucocerebrosidase, presents with a wide range of symptoms of varying severity, and primarily affects the skeletal, hematologic and nervous systems. To date, the standard of care has included enzyme replacement therapy with imiglucerase. Although imiglucerase is highly effective in reversing the visceral and hematologic manifestations, skeletal disease is slow to respond, pulmonary involvement is relatively resistant, and the CNS involvement is not impacted. Because of the recent manufacturing and processing problems, the research and development of alternative therapeutics has become more pressing. The divergent phenotypes and the heterogeneity involving different organ systems implicates the involvement of several pathological processes that include enzyme deficiency, substrate accumulation, protein misfolding, and macrophage activation, that differ in each patient with GD. Thus, the therapy should be tailored individually in order to target multiple pathways that interplay in GD.

Keywords: enzyme replacement therapy; glucocerebrosidase; macrophage; protein misfolding and chaperone therapy; substrate reduction therapy.

References

    1. Goker-Alpan O, Schiffmann R, Park JK, Stubblefield BK, Tayebi N, Sidransky E. Phenotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3. J Pediatr. 2003;143:273–276.
    1. Barneveld RA, Keijzer W, Tegelaers FP, et al. Assignment of the gene coding for human beta-glucocerebrosidase to the region q21–q31 of chromosome 1 using monoclonal antibodies. Hum Genet. 1893;64:227–231.
    1. Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA) Hum Mutat. 2008;29:567–583.
    1. Goker-Alpan O, Hruska KS, Orvisky E, et al. Divergent phenotypes in Gaucher disease implicate the role of modifiers. J Med Genet. 2005;42:e37.
    1. Lachmann RH, Grant IR, Halsall D, Cox TM. Twin pairs showing discordance of phenotype in adult Gaucher’s disease. QJM. 2004;97:199–204.
    1. Hruska KS, LaMarca ME, Sidransky E. In: Gaucher Disease. Futerman AH, Zimran A, editors. Boca Raton, FL: CRC Press; 2006. pp. 13–48.
    1. Beutler E, Grabowski GA, Scriver CR, Beaudet AL, Valle D, Sly WS, editors. The Metabolic and Molecular Bases of Inherited Diseases. New York, NY: McGraw-Hill; 2001.
    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 Neuropathologica. 2004;75:385–390.
    1. Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher disease: a review. Br J Radiol. 2002;75(Suppl 1):A2–A12.
    1. Goitein O, Elstein D, Abrahamov A, et al. Lung involvement and enzyme replacement therapy in Gaucher’s disease. Q J Med. 2001;94:407–415.
    1. Kaplan P, Andersson HC, Kacena KA, Yee JD. The clinical and demographic characteristics of non-neuronopathic Gaucher disease in 887 children at diagnosis. Arch Pediatr Adolesc Med. 2006;160:603–608.
    1. Ginns EI, Choudary PV, Tsuji S, et al. Gene mapping and leader polypeptide sequence of human glucocerebrosidase: implications for Gaucher disease. Proc Natl Acad Sci U S A. 1985;82:7101–7105.
    1. Berg-Fussman A, Grace ME, Ioannou Y, Grabowski GA. Human acid beta-glucosidase. N-glycosylation site occupancy and the effect of glycosylation on enzymatic activity. J Biol Chem. 1993;268:14861–14866.
    1. Grabowski GA, Gatt, Horowitz M. Acid β-glucosidase: enzymology and molecular biology of Gaucher disease. Crit Rev Biochem Mol Biol. 1990;25:385–414.
    1. Vaccaro AM, Tatti M, Ciaffoni F, Salvioli R, Barca A, Scerch C. Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide. J Biol Chem. 1990;272:16862–16867.
    1. Morimoto S, Kishimoto Y, Tomich J, et al. Interaction of Saposins, Acid Lipids, and Glucosylceramidase. J Biol Chem. 1990;265:1933–1937.
    1. Premkumar L, Sawkar AR, Boldin-Adamsky S, et al. X-ray structure of human acid beta-glucosidase covalently bound to conduritol-β-epoxide. Implications for Gaucher disease. J Biol Chem. 2005;280:23815–23819.
    1. Dvir H, Harel M, McCarthy AA, et al. X-ray structure of human acid β-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep. 2003;2003:704–709.
    1. Grace ME, Graves PN, Smith FI, Grabowski GA. Analysis of catalytic and inhibitor binding of human acid beta-glucosidase by site directed mutagenesis. J Biol Chem. 1994;256:6827–6835.
    1. Salvioloi R, Tatti M, Scarpa S, et al. The N370S (Asn370Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C. Biochem J. 2005;390:95–103.
    1. De Duve C. From cytases to hydrolases. Federation Proceedings. 1964;23:1045–1049.
    1. Frantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968;162:468–572.
    1. Brady RO, Pentchev PG, Gal AE, Hibbert SR, Dekaban AS. Replacement therapy for inherited enzyme deficiency. Use of purified glucocerebrosidase in Gaucher’s disease. N Engl J Med. 1974;291:989–993.
    1. Furbish FS, Steet CJ, Barranger JA, Jones EA, Brady RO. The uptake of naive and desialylated glucocerebrosidase by rate hepatocytes and Kupffer cells. Biochem Biophys Res Commun. 1978;81:1047–1053.
    1. Beutler E, Kuhl W, Vaughan LM. Failure of alglucerase infused into Gaucher disease patients to localize in marrow macrophages. Mol Med. 1995;1:320–324.
    1. Doebber TW, Wu MS, Bugianesi RL, et al. Enhanced macrophage uptake of synthetically glycosylated human placental β-glucocerebrosidase. J Biol Chem. 1982;252:2193–2199.
    1. Sato Y, Beutler E. Binding, internalization and degradation of mannose terminated glucocerebrosidase by macrophages. J Clin Invest. 1993;91:1909–1917.
    1. Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiency-macrophage targeted glucocerebroidase for Gaucher’s disease. N Engl J Med. 1991;234:1464–1470.
    1. Xu YH, Ponce E, Sun Y, Leonova T, Bove K, Witte D, Grabowski GA. Turnover and distribution of intravenously administered mannose-terminated human acid beta-glucosidase in murine and human tissues. Pediatr Res. 1996;39:313–322.
    1. Mistry PK, Wraight EP, Cox TM. Therapeutic delivery of proteins to macrophages:Implications for treatment of Gaucher’s disease. Lancet. 1996;348:1555–1559.
    1. Grabowski GA, Kacena K, Cole JA, et al. Dose response relationships for enzyme replacement therapy with imiglucerase/aglucerase in patients with Gaucher disease type 1. Genet Med. 2009;11:92–100.
    1. Altarescu G, Schiffmann R, Parker CC, et al. Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease. Blood Cells Mol Dis. 2000;26:285–290.
    1. Figueroa ML, Rosenbloom BE, Kay AC, et al. A less costly regimen of aglucerase to treat Gaucher’s disease. N Engl J Med. 1992;327:1632–1636.
    1. Zimran A, Hadas-Halpern I, Zevin S, Levy-Lahad E, Abrahamov A. Low-dose high-frequency enzyme replacement therapy for very young children with severe Gaucher disease. Br J Haematol. 1993;85:783–786.
    1. Wilson C, Spearing R, Teague L, Robertson P, Blacklock H. The outcome of clinical parameters in adults with severe Type I Gaucher disease using very low dose enzyme replacement therapy. Mol Genet Metab. 2007;92:131–136.
    1. de Fost M, Aerts J, Groener JEM, et al. Low frequency maintenance therapy with imiglucerase in adult type I Gaucher disease: a prospective randomized controlled trial. Haematologica. 2007;92:215–221.
    1. Kishnani PS, DiRocco M, Kaplan P, et al. A randomized trial comparing the efficacy and safety of imiglucerase (Cerezyme) infusions every 4 weeks versus every 2 weeks in maintenance therapy of adult patients with Gaucher disease type 1. Mol Genet Metab. 2009;96:164–170.
    1. Pastores GM, Weinreb NJ, Aerts G, et al. Semin Hematol. 2004;41(Suppl 5):4–14.
    1. Dweck A, Abrahamov A, Hadas-Halpern I, Bdolach-Avram T, Zimran A, Elstein D. Type I Gaucher disease in children with and without enzyme therapy. Pediatr Hematol Onco. 2002;6:389–397.
    1. Andersson H, Kaplan P, Kacena K, Yee J. Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease Type 1. Pediatrics. 2008;122:1182–1190.
    1. Charrow J, Andersson HC, Kaplan P, et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr. 2004;144:112–120.
    1. Grabowski GA, Andria G, Baldellou A, et al. Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements. Eur J Pediatr. 2004;163:58–66.
    1. Brunel-Guitton C, Rivard GE, Galipeau J, et al. Enzyme replacement therapy in pediatric patients with Gaucher disease: what should we use as maintenance dosage? Mol Gen Metab. 2009;96:73–76.
    1. Baldellou A, Andria G, Campbell PE, et al. Paediatric non-neuronopathic Gaucher disease: recommendations for treatment and monitoring. Eur J Pediatr. 2004;163:67–75.
    1. de Fost M, van Noesel CJM, Johannes MFG, et al. Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of enzyme replacement therapy. Hematologica. 2008;93:119–1120.
    1. Mistry PK, Sirrs S, Chan A, et al. Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab. 2002;77:91–98.
    1. Campbell PE, Harris CM, Vellodi A. Deterioration of the auditory brainstem response in children with type 3 Gaucher disease. Neurology. 2004;63:385–387.
    1. Vellodi A, Tylki-Szymanska A, Davies EH, et al. Management of neuronopathic Gaucher disease: revised recommendations. J Inherit Metab Dis. 2009;32:660–664.
    1. Schiffmann R, Heyes MP, Aerts JM, et al. Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher’s disease. Ann Neurol. 1997;42:613–621.
    1. Brumshtein B, Salinas P, Peterson B, et al. Characterization of gene-activated human acid-β-glucosidase:crystal structure, glycan composition and internalization into macrophages. Glycobiology. 2010;20:24–32.
    1. Shaaltiel Y, Bartfeld D, Hashmueli S, et al. Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher’s disease using a plant cell system. Plant Biotechnol J. 2007;5:579–590.
    1. Zimran A, Loveday K, Fratazzi C, Elstein D. A pharmacokinetic analysis of a novel enzyme replacement therapy with gene-activated human glucocerebrosidase (GA-GCB) in patients with type 1 Gaucher disease. Blood Cells Mol Dis. 2007;39:115–118.
    1. Scott M, van Patten SM, Hughes H, et al. Effect of mannose chain length on targeting of glucocerebrosidase for enzyme replacement therapy of Gaucher disease. Glycobiology. 2007;17:467–478.
    1. Aviezer D, Brill-Almon E, Yoseph Shaaltiel Y, et al. Plant-derived recombinant human glucocerebrosidase enzyme – a preclinical and phase I investigation. PLoS ONE. 2009;4:e4792.
    1. Penneli N, Scaravilli F, Zacchello F. Morphogenesis of Gaucher cells investigated by electron microscopy. Blood. 1969;34:331–347.
    1. Nillson O, Hakansson G, Dreborg S, Groth CG, Svernerholm L. Increased cerebroside concentration in plasma and erythrocytes in Gaucher disease: significant differences between type I and type III. Clin Gene. 1982;22:274–279.
    1. Cox T, Lachmann R, Hollak CM, et al. Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycine (OGT 918) to decrease substrate biosynthesis. Lancet. 2000;355:1481–1485.
    1. Hollak CEM, Hughes D, van Schaik IV, Schwierin B, Bembi B. Miglustat (Zavesca®) in type 1 Gaucher disease: 5-year results of a post-authorization safety. Pharmacoepidem Dr S. 2009;18:770–777.
    1. Platt FM, Neises GR, Reikenmeiser G, et al. Prevention of lysosomal storage disease in Tay Sachs mice treated with N-butyldeoxynojirimycin. Science. 1997;276:428–431.
    1. Shiffmann 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. Futerman AH, Hannun YA. The complex life of simple sphingolipids. EMBO Rep. 2004;5:777–782.
    1. Thompson A, Barrow CJ. Protein conformational misfolding and amyloid formation: characteristics of a new class of disorders that include Alzheimer’s and prion diseases. Curr Med Chem. 2002;9:1751–1762.
    1. Gregersen N. Protein misfolding disorders: pathogenesis and intervention. J Inherit Metab Dis. 2006;29:456–470.
    1. Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006;75:333–366.
    1. Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. 2004;81:70–73.
    1. Goker-Alpan O, Schiffmann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E. Parkinsonism among Gaucher disease carriers. J Med Genet. 2004;41:937–940.
    1. Goker-Alpan O, Giasson BI, Eblan MJ, et al. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology. 2006;67:908–910.
    1. Fan JQ. A contradictory treatment for lysosomal storage disorders: inhibitors enhance mutant enzyme activity. Trends Pharmacol Sci. 2003;24:355–360.
    1. Butters TD. Pharmacotherapeutic strategies using small molecules for the treatment of glycolipid lysosomal storage disorders. Expert Opin Pharmacother. 2007;8:427–435.
    1. Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW. Chemical chaperones increase the cellular activity of N370S β-glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci U S A. 2002;99:15428–31543.
    1. Chang HH, Asano N, Ishii S, Ichikawa Y, Fan JQ. Hydrophilic imino sugar active-site-specific chaperones increase residual glucocerebrosidase activity in fibroblasts from Gaucher patients. FEBS J. 2006;273:4082–4092.
    1. Steet RA, Chung S, Wustman B, Powe A, Do H, Kornfeld SA. The imino sugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms. Proc Natl Acad Sci U S A. 2006;103:13813–13818.
    1. Sawkar AR, Adamski-Werner SL, Cheng WC, et al. Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles. Chem Biol. 2005;12:1235–1244.
    1. Stanley P, Sundaram S, Tang J, Shi S. Molecular analysis of three gain-of-function CHO mutants that add the bisecting GlcNAc to N-glycans. Glycobiology. 2005;15:43–53.
    1. Khanna R, Benjamin ER, Pellegrino L, et al. The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of beta-glucosidase. FEBS J. 2010;277(7):1618–1638.
    1. Steet R, Chung S, Lee WS, Pine CW, Do H, Kornfeld S. Selective action of the imino sugar isofagomine, a pharmacological chaperone for mutant forms of acid-beta-glucosidase. Biochem Pharmacol. 2007;73:1376–1383.
    1. Mu TW, Fowler DM, Kelly JW. Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis. PLoS Biol. 2008;6:e26.
    1. Rigat B, Mahuran D. Diltiazem, a L-type Ca(2+) channel blocker, also acts as a pharmacological chaperone in Gaucher patient cells. Mol Genet Metab. 2009;96:225–232.
    1. Sun Y, Liou B, Quinn B, Ran H, Xu YH, Grabowski GA. In vivo and ex vivo evaluation of L-type calcium channel blockers on acid beta-glucosidase in Gaucher disease mouse models. PLoS One. 2009;4:e7320.
    1. Zheng W, Padia J, Urban DJ, et al. Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease. PNAS. 2007;104:13192–13197.
    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. Moller HJ, DeFost M, Aerts H, Hollak C, Moestrup SK. Plasma level of the macrophage-derived soluble CD163 is increased and positively correlates with severity in Gaucher’s disease. Eur J Haematol. 2004;72:135–139.
    1. Boven LA, van Meurs M, Boot RG, et al. Gaucher cells demonstrate a distinct macrophage phenotype and resemble alternatively activated macrophages. Am J Clin Pathol. 2004;122:359–369.
    1. Douglas B, Robinson RH, Glew A. Tartrate-resistant acid phosphatase from gaucher spleen. J Biol Chem. 1980;255:5864–5870.
    1. Silverstein E, Pertschuk LP, Friedland J. Immunofluorescent detection of angiotensin-converting enzyme (ACE) in Gaucher cells. Am J Med. 1980;69:408–410.
    1. Hollak CEM, Maas M, Aerts JM. Clinically relevant therapeutic endpoints in type I Gaucher disease. J Inherit Metab Dis. 2001;24(Suppl 2):97–105.
    1. Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity: a novel hallmark of Gaucher disease. J Clin Invest. 1994;93:1288–1292.
    1. Boot RG, Verhoek M, Langeveld M, et al. CCL18: a urinary marker of Gaucher cell burden in Gaucher patients. J Inherit Metab Dis. 2006;29(4):564–571.
    1. Aerts JM, van Breemen MJ, Bussink AP, et al. Biomarkers for lysosomal storage disorders: identification and application as exemplified by chitotriosidase in Gaucher disease. Acta Paediatr. 2008;97:7–14.
    1. Moran MT, Schofield JP, Hayman AR, Shi GP, Young E, Cox TM. Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic cathepsin K. Blood. 2000;96:1969–1978.
    1. Rogowski O, Shapira I, Zimran A, et al. Automated system to detect low-grade underlying inflammatory profile: Gaucher disease as a model. Blood Cells Mol Dis. 2005;34:26–29.
    1. Herman S, Krönke G, Schett G. Molecular mechanisms of inflammatory bone damage, emerging trends for therapy. Trends Mol Med. 2008;14(6):245–253.
    1. Bargagli E, Margollicci M, Nikiforakis N, et al. Chitotriosidase activity in the serum of patients with sarcoidosis and pulmonary tuberculosis. Respiration. 2007;74:548–552.
    1. Boot RG, Hollak CE, Verhoek M, Alberts C, Jonkers RE, Aerts JM. Plasma chitotriosidase and CCL18 as surrogate markers for granulomatous macrophages in sarcoidosis. Clin Chim Acta. 2010;411:31–36.
    1. Bargagli E, Maggiorelli C, Rottoli P. Chitotriosidase in patients with interstitial lung disease. Respiration. 2008;76:234–238.
    1. Goker-Alpan O, Giasson BI, Eblan MJ, et al. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology. 2006;67:908–910.
    1. Goker-Alpan O, Lopez G, Vithayathl J, Davis J, Hallett M, Sidransky E. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol. 2008;65:1353–1357.
    1. Gan-Or Z, Giladi N, Rozovski U, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008;70:2277–2283.

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