The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases
2014; Elsevier BV; Volume: 55; Issue: 7 Linguagem: Inglês
10.1194/jlr.r047167
ISSN1539-7262
AutoresJames A. Shayman, Scott D. Larsen,
Tópico(s)Sphingolipid Metabolism and Signaling
ResumoGlycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials. Two primary alternative strategies that have been pursued include pharmacological chaperones and GSL synthase inhibitors. There are theoretical advantages and disadvantages to each of these approaches. Pharmacological chaperones are specific for an individual glycoside hydrolase and for the specific mutation present, but no candidate chaperone has been demonstrated to be effective for all mutations leading to a given disorder. Synthase inhibitors target single enzymes such as glucosylceramide synthase and inhibit the formation of multiple GSLs. A glycolipid synthase inhibitor could potentially be used to treat multiple diseases, but at the risk of lowering nontargeted cellular GSLs that are important for normal health. The basis for these strategies and specific examples of compounds that have led to clinical trials is the focus of this review. Glycosphingolipid (GSL) storage diseases have been the focus of efforts to develop small molecule therapeutics from design, experimental proof of concept studies, and clinical trials. Two primary alternative strategies that have been pursued include pharmacological chaperones and GSL synthase inhibitors. There are theoretical advantages and disadvantages to each of these approaches. Pharmacological chaperones are specific for an individual glycoside hydrolase and for the specific mutation present, but no candidate chaperone has been demonstrated to be effective for all mutations leading to a given disorder. Synthase inhibitors target single enzymes such as glucosylceramide synthase and inhibit the formation of multiple GSLs. A glycolipid synthase inhibitor could potentially be used to treat multiple diseases, but at the risk of lowering nontargeted cellular GSLs that are important for normal health. The basis for these strategies and specific examples of compounds that have led to clinical trials is the focus of this review. The maintenance of cellular homeostasis requires the continuous synthesis, degradation, and recycling of a variety of cellular molecules that include lipids, proteins, glycoproteins, glycolipids, and oligosaccharides. Many of the enzymes responsible for the catabolism of these compounds are localized to the lysosome where they function in an acidic environment (1Schulze H. Sandhoff K. Sphingolipids and lysosomal pathologies.Biochim. Biophys. Acta. 2013; Google Scholar). When lysosomal function is disrupted either through loss of activity of a critical lysosomal protein such as a transporter or ATPase, or due to an inherited or acquired loss of function of a lysosomal hydrolase, the accumulation of one or more of these metabolic intermediates may occur with significant pathological consequences. There are more than 50 lysosomal storage diseases (LSDs) that can arise in this way (2Futerman A.H. van Meer G. The cell biology of lysosomal storage disorders.Nat. Rev. Mol. Cell Biol. 2004; 5: 554-565Crossref PubMed Scopus (628) Google Scholar). Among the pathways that can be affected are those associated with glycosphingolipid (GSL) catabolism. Among those, "glycosphingolipidoses" that have been recognized as LSDs are Gaucher disease types 1, 2, and 3, Fabry disease, Tay-Sachs and Sandhoff disease, and GM1 gangliosidosis. These LSDs are alike in that the lipid substrate that accumulates in the lysosome is either glucosylceramide or a glucosylceramide-based lipid (Table 1). These GSL storage diseases are pleiotropic with regard to their clinical phenotypes (3Meikle P.J. Hopwood J.J. Clague A.E. Carey W.F. Prevalence of lysosomal storage disorders.JAMA. 1999; 281: 249-254Crossref PubMed Scopus (1710) Google Scholar). Their wide clinical spectrum may be based on the biological role of a specific GSL in an affected organ or cell type, due to modifying factors such as secondary genes or, in the case of X-linked diseases such as Fabry disease and Barr body inactivation (4Sandhoff K. Harzer K. Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis.J. Neurosci. 2013; 33: 10195-10208Crossref PubMed Scopus (192) Google Scholar, 5Cox T.M. Cachon-Gonzalez M.B. The cellular pathology of lysosomal diseases.J. Pathol. 2012; 226: 241-254Crossref PubMed Scopus (160) Google Scholar). Additionally, the severity of the clinical phenotype may be the result of secondary and often irreversible pathological changes that lead to clinically significant and intractable disease. Each of the glycosphingolipidoses is associated with both peripheral and CNS manifestations.TABLE 1The glucosylceramide based GSL storage diseasesDiseaseEnzyme DeficiencyAccumulating SubstrateClinical PhenotypeGaucherβ-glucosidase (GBA)GlucosylceramideSplenomegaly, hepatomegaly, anemia, thrombocytopenia, bone disease (type 1); seizures, cognitive impairment (types 2 and 3)FabryGLAGb3, galabiosylceramide, lyso-Gb3Stroke, renal failure, cardiac disease, acroparasthesias, angiokeratomasTay-Sachsβ-hexosaminidase AGanglioside GM2, chondroitin sulfateBlindness, deafness, muscle atrophy, paralysis (infantile form); dysarthria, aphasia, ataxia, cognitive decline, psychosis (juvenile and adult onset)Sandhoffβ-hexosaminidase A/BGanglioside GM2, globoside, gangliotriaosylceramideIndistinguishable from Tay-Sachs diseaseGM1 gangliosidosisβ-galactosidaseGanglioside GM1Neurodegeneration, seizures, blindness, deafness, hepato- and splenomegaly Open table in a new tab Considerable attention has been focused over the last 30 years on the development of therapies for the treatment of glycosphingolipidoses. Understandably, the initial efforts to develop therapies for LSDs were focused on enzyme replacement strategies based on the view that this would provide the most specific and efficacious therapeutic result. Seminal work by Kornfeld and Kornfeld (6Kornfeld R. Kornfeld S. Assembly of asparagine-linked oligosaccharides.Annu. Rev. Biochem. 1985; 54: 631-664Crossref PubMed Scopus (3772) Google Scholar) and Stahl (7Stahl P.D. The mannose receptor and other macrophage lectins.Curr. Opin. Immunol. 1992; 4: 49-52Crossref PubMed Scopus (223) Google Scholar) identified the role of mannose and mannose 6-phosphate in lysosomal protein sorting and cellular recognition and uptake. Subsequent efforts by Brady et al. (8Brady R.O. Pentchev P.G. Gal A.E. Hibbert S.R. Dekaban A.S. Replacement therapy for inherited enzyme deficiency. Use of purified glucocerebrosidase in Gaucher's disease.N. Engl. J. Med. 1974; 291: 989-993Crossref PubMed Scopus (207) Google Scholar) established that mannose-terminated lysosomal glucocerebrosidase could be used as the basis for enzyme replacement in Gaucher disease type 1. For some GSL storage diseases, including Gaucher disease type I and Fabry disease, enzyme replacement therapy (ERT) has subsequently been established as the standard of care (9Brady R.O. Enzyme replacement for lysosomal diseases.Annu. Rev. Med. 2006; 57: 283-296Crossref PubMed Scopus (239) Google Scholar). However, ERT has several limitations. These include a very high cost (10Beutler E. Lysosomal storage diseases: natural history and ethical and economic aspects.Mol. Genet. Metab. 2006; 88: 208-215Crossref PubMed Scopus (78) Google Scholar), the requirement for intravenous administration, the failure of the infused protein to distribute adequately to target tissues, the development of antibodies to the enzyme resulting in loss of therapeutic efficacy, and the inability of the lysosomal protein to cross the blood-brain barrier. Due to this last property, LSDs in those individuals that have CNS involvement, including Gaucher disease types 2 and 3, the GM2 gangliosidoses (Tay-Sachs and Sandhoff disease), and GM1 gangliosidosis are unresponsive to ERT (11Bennett L.L. Mohan D. Gaucher disease and its treatment options.Ann. Pharmacother. 2013; 47: 1182-1193Crossref PubMed Scopus (76) Google Scholar). Other strategies for "enzyme replacement" in addition to the use of recombinant mannose-terminated enzyme have been explored. These include bone marrow transplantation (12Ohshima T. Schiffmann R. Murray G.J. Kopp J. Quirk J.M. Stahl S. Chan C.C. Zerfas P. Tao-Cheng J.H. Ward J.M. et al.Aging accentuates and bone marrow transplantation ameliorates metabolic defects in Fabry disease mice.Proc. Natl. Acad. Sci. USA. 1999; 96: 6423-6427Crossref PubMed Scopus (86) Google Scholar), gene therapy (13Sardi S.P. Clarke J. Viel C. Chan M. Tamsett T.J. Treleaven C.M. Bu J. Sweet L. Passini M.A. Dodge J.C. et al.Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for Parkinsonism and other Gaucher-related synucleinopathies.Proc. Natl. Acad. Sci. USA. 2013; 110: 3537-3542Crossref PubMed Scopus (178) Google Scholar, 14Yoshimitsu M. Higuchi K. Ramsubir S. Nonaka T. Rasaiah V.I. Siatskas C. Liang S.B. Murray G.J. Brady R.O. Medin J.A. Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells.Gene Ther. 2007; 14: 256-265Crossref PubMed Scopus (40) Google Scholar), and more recently stem cell therapy (15Enquist I.B. Nilsson E. Mansson J.E. Ehinger M. Richter J. Karlsson S. Successful low-risk hematopoietic cell therapy in a mouse model of type 1 Gaucher disease.Stem Cells. 2009; 27: 744-752Crossref PubMed Scopus (30) Google Scholar). However, none of these approaches have yet to become the basis for clinical practice. The limitations of ERT have led several groups to explore alternative strategies, including the use of small chemical entities. Among the alternatives considered are chemical chaperones and GSL synthesis inhibitors. A number of comprehensive reviews in this field have recently been published (16Boyd R.E. Lee G. Rybczynski P. Benjamin E.R. Khanna R. Wustman B.A. Valenzano K.J. Pharmacological chaperones as therapeutics for lysosomal storage diseases.J. Med. Chem. 2013; 56: 2705-2725Crossref PubMed Scopus (163) Google Scholar, 17Suzuki Y. Chaperone therapy update: Fabry disease, GM1-gangliosidosis and Gaucher disease.Brain Dev. 2013; 35: 515-523Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 18Weinreb N.J. Oral small molecule therapy for lysosomal storage diseases.Pediatr. Endocrinol. Rev. 2013; 11: 77-90PubMed Google Scholar, 19Shayman J.A. The design and clinical development of inhibitors of glycosphingolipid synthesis: will invention be the mother of necessity?.Trans. Am. Clin. Climatol. Assoc. 2013; 124: 46-60PubMed Google Scholar). Therefore this review will highlight selected examples in the discovery and development of compounds that have been the subject of clinical trials. LSDs can arise from any one of several defects reflecting the complex series of events that must occur for the proper translation, folding, posttranslational processing, and trafficking of lysosomal enzymes. These defects include improper enzyme complex assembly (galactosialidosis) (20Ostrowska H. Krukowska K. Kalinowska J. Orlowska M. Lengiewicz I. Lysosomal high molecular weight multienzyme complex.Cell. Mol. Biol. Lett. 2003; 8: 19-24PubMed Google Scholar), protein misfolding (Gaucher, Fabry disease) resulting in recognition by the endoplasmic reticulum (ER) quality control system with premature degradation (17Suzuki Y. Chaperone therapy update: Fabry disease, GM1-gangliosidosis and Gaucher disease.Brain Dev. 2013; 35: 515-523Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar), improper enzyme glycosylation and sorting (I cell disease), missense mutations resulting in decreased catalytic activity (Gaucher, Fabry, Niemann-Pick disease), the absence of an activator protein (GM2 gangliosidosis) (21Mahuran D.J. Biochemical consequences of mutations causing the GM2 gangliosidoses.Biochim. Biophys. Acta. 1999; 1455: 105-138Crossref PubMed Scopus (236) Google Scholar), defective intrinsic membrane function (LAMP2 and Danon disease) (22Nishino I. Fu J. Tanji K. Yamada T. Shimojo S. Koori T. Mora M. Riggs J.E. Oh S.J. Koga Y. et al.Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).Nature. 2000; 406: 906-910Crossref PubMed Scopus (725) Google Scholar), and the loss of transporter activity (cystinosis) (23Mancini G.M. Havelaar A.C. Verheijen F.W. Lysosomal transport disorders.J. Inherit. Metab. Dis. 2000; 23: 278-292Crossref PubMed Scopus (44) Google Scholar). The glycosphingolipidoses are a subset of LSDs that are characterized by the lysosomal accumulation of one or more species of GSLs. The clinical phenotypes are distinct and vary based on the affected enzyme or activator, the function of the glycolipids that accumulate, the cell types and tissues affected, and the degree of residual lysosomal hydrolase activity. Depending on the type of mutation underlying the genetic basis for a given disease, there may be either the total or incomplete loss of hydrolase activity. For example, a nonsense mutation resulting in a premature stop codon or partial gene deletion may lead to the translation of a protein with no measurable function. Alternatively, a missense mutation may lead to either the biosynthesis of an enzyme that lacks normal catalytic activity or a misfolded protein that is rapidly degraded following biosynthesis. Thus, the therapeutic approach to the treatment of any particular LSD will depend on the nature of the primary inherited defect. Those disorders associated with a complete loss of enzyme activity, either due to the incomplete translation or the formation of a catalytically dead glycoside hydrolase, will likely require the replacement of the absent or inactive enzyme. Disorders in which misfolded protein is targeted for degradation may be amenable to therapies that limit this degradation, such as pharmacological chaperones (24Parenti G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics.EMBO Mol. Med. 2009; 1: 268-279Crossref PubMed Scopus (217) Google Scholar). Finally, disorders in which some residual lysosomal glycoside hydrolase activity persists may potentially be treated with a GSL synthesis inhibitor (25Radin N.S. Treatment of Gaucher disease with an enzyme inhibitor.Glycoconj. J. 1996; 13: 153-157Crossref PubMed Scopus (108) Google Scholar). Gaucher disease, Fabry disease, the GM2 gangliosidoses (Tay-Sachs and Sandhoff disease), and GM1 gangliosidosis are characterized by the lysosomal accumulation of glucosylceramide, globotriaosylceramide (Gb3), lyso-Gb3, ganglioside GM2, and ganglioside GM1, respectively, due to a deficiency in a specific lysosomal hydrolase or subunit. For Gaucher type 1 disease there is invariably residual activity of β-glucocerebrosidase (GBA); for Fabry disease and GM1 gangliosidosis there may or may not be residual activity of α-galactosidase A (GLA) or of β-galactosidase, respectively. While genotype/phenotype correlations have at times been difficult to establish, in general there is a correlation between the residual activity and the clinical phenotype. For example, the level of residual β-galactosidase activity determines the age of onset for GM1 gangliosidosis (26Suzuki Y. Ogawa S. Sakakibara Y. Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities.Perspect. Medicin. Chem. 2009; 3: 7-19Crossref PubMed Google Scholar). The residual GBA activity is one determinant of the presence and severity of CNS involvement in Gaucher disease types 2 and 3 (27Sidransky E. Gaucher disease: insights from a rare Mendelian disorder.Discov. Med. 2012; 14: 273-281PubMed Google Scholar). The likelihood of developing end stage renal disease is correlated with the presence or absence of GLA activity (28Branton M. Schiffmann R. Kopp J.B. Natural history and treatment of renal involvement in Fabry disease.J. Am. Soc. Nephrol. 2002; 13: S139-S143Crossref PubMed Google Scholar). In evaluating different therapeutic strategies for the treatment of these GSLs, it is important to consider the pathways of GSL metabolism. For Gaucher disease, Fabry disease, Tay-Sachs disease, and GM1 gangliosidosis, all of the accumulating GSLs arise from glucosylceramide as the core cerebroside (Fig. 1A). Gb3, a neutral lipid, is formed by the sequential addition of two galactose sugars. The gangliosides, on the other hand, are formed as part of a combinatorial pathway in which two sialyltransferases (SATs) with a high degree of substrate specificity, St3gal5 and St8sia1 (SATI and SATII), add one, two, or three sialic acids to lactosylceramide forming gangliosides GM3, GD3, and GT3 (29Kolter T. Proia R.L. Sandhoff K. Combinatorial ganglioside biosynthesis.J. Biol. Chem. 2002; 277: 25859-25862Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). These gangliosides can in turn be further glycosylated by a series of much less specific glycosyltransferases resulting in the formation of a limited series of more complex gangliosides (Fig. 1B).Fig. 1A: General pathways for synthesis of GSLs from ceramide. B: Pathways for the synthesis of O-, a-, b-, and c-series GSLs. The a-, b-, and c-series glycolipids are distinguished by the presence of one or more sialic acids. The stepwise addition of sialylation of lactosylceramide by GM3 synthase (SAT I), St8sia1 (SAT II), and St8sia5 (SAT III) results from enzymes with narrow substrate specificity. By contrast, the synthesis of more fully glycosylated GSLs is catalyzed by enzymes of comparably broad specificity. Thus inhibition of any one enzyme associated with GSL synthesis will lower multiple species of glycolipids.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In principle, for any specific LSD, either the restoration of the defective hydrolase or the inhibition of a synthetic enzyme that is proximate to the accumulating GSL should result in decreased lysosomal GSL content. For example, in Gaucher disease arising from the loss of GBA activity, either the replacement of the deficient enzyme or the inhibition of glucosylceramide synthase could lower glucosylceramide content. In Fabry disease, Gb3 levels would fall with the replacement of GLA or inhibition of either glucosylceramide synthase or lactosylceramide synthase (B4GalT1). Alternatively, a GM2 or GM1 gangliosidosis could be treated with the replacement of hexosaminidase A or B (depending on whether Tay-Sachs or Sandhoff disease was present), by β-galactosidase enzyme, or by inhibition of any number of upstream glycosyltransferases (Fig. 2). Glucosylceramide is the precursor for most of the gangliosides and globo series GSLs. Due to the limited specificity of additional GSL synthases in the formation of more complex gangliosides, there is no single synthase enzyme that can be successfully targeted without resulting in the lowering of several additional GSLs. Because each GSL may have one or more distinctly important biological functions, this lack of specificity is a theoretical limitation for substrate deprivation or synthesis inhibition therapy. By contrast, chaperone therapy or enzyme replacement strategies specifically target the deficient hydrolase. If an exogenously delivered enzyme can be delivered to the lysosomes of affected cells and targeted tissues, then the clinical disease may be prevented, reversed, or mitigated. Alternatively, if a chemical chaperone can result in the restoration of the enzyme activity of the endogenously produced misfolded hydrolase to which it binds, then a beneficial clinical response may also occur. The glycoside hydrolases required for the proper metabolism of GSLs are synthesized and folded within the ER, exported to the Golgi apparatus, and trafficked to the lysosome. When a missense mutation resulting in a single amino acid substitution occurs, there may be misfolding of the protein even when these substitutions are at sites of the hydrolase that are remote from the catalytic domain. Because efficient trafficking requires correctly folded proteins, the ER quality control system will retain the misfolded protein within the ER or redirect it for proteasomal degradation. Pharmacological chaperones in the form of small molecule inhibitors of the hydrolase bind to the nascent protein within the ER resulting in an increase in the steady state levels of the enzyme. Several general mechanisms can be considered for how chemical chaperones might actually work to improve the trafficking of hydrolases (30Lieberman R.L. D'aquino J.A. Ringe D. Petsko G.A. Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability.Biochemistry. 2009; 48: 4816-4827Crossref PubMed Scopus (121) Google Scholar). The chaperone could bind to the misfolded mutant protein allowing for greater stability of the protein than would normally occur with the particular substitution. The chaperone might bind to the mutant protein as it is being folded from its nonnative intermediate state to a native-like state. This native-like state would be sufficiently similar to the properly folded native protein to avoid the ER quality control system. The chaperone might allow for the proper posttranslational modifications in the form of protein glycosylation to occur. The chaperone might allow for the proper dimerization to occur, as in the case of GLA. The chaperone might permit the proper binding of an activator protein in the form of a saposin. The chaperone might protect the mutated protein from misfolding due to a change in pH or might inhibit premature degradation by a protease. Whether one or more of these mechanisms is the basis for the activity of the chaperone presumably depends on both the specific hydrolase in question and the particular mutation present. Imino sugars have been the focus of significant drug development efforts due to their potential use as both glucosylceramide synthase inhibitors and pharmacological chaperones. However, the imino sugars were originally identified as α-glucosidase inhibitors and developed for their potential for anti-viral activity. N-butyldeoxynojiromycin (NB-DNJ, miglustat, Zavesca™) is the prototypic compound, observed to inhibit glucosylceramide synthase at concentrations that vary between 20 and 50 üM depending on the cell type and assay employed (31Platt F.M. Neises G.R. Dwek R.A. Butters T.D. N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis.J. Biol. Chem. 1994; 269: 8362-8365Abstract Full Text PDF PubMed Google Scholar, 32Wennekes T. Meijer A.J. Groen A.K. Boot R.G. Groener J.E. van Eijk M. Ottenhoff R. Bijl N. Ghauharali K. Song H. et al.Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation.J. Med. Chem. 2010; 53: 689-698Crossref PubMed Scopus (87) Google Scholar). In addition to α-glucosidase, a significant number of off target effects have been reported. Enzymes other than glucosylceramide synthase that are inhibited at micromolar concentrations of drug include lysosomal GBA, non-lysosomal GBA2 (33Ridley C.M. Thur K.E. Shanahan J. Thillaiappan N.B. Shen A. Uhl K. Walden C.M. Rahim A.A. Waddington S.N. Platt F.M. et al.β-Glucosidase 2 (GBA2) activity and imino sugar pharmacology.J. Biol. Chem. 2013; 288: 26052-26066Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), glycogen debranching enzyme, and sucrase. In addition, miglustat causes cellular depletion of lymphoid organs in WT mice (34Platt F.M. Reinkensmeier G. Dwek R.A. Butters T.D. Extensive glycosphingolipid depletion in the liver and lymphoid organs of mice treated with N-butyldeoxynojirimycin.J. Biol. Chem. 1997; 272: 19365-19372Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). Early "proof of concept" studies in Tay-Sachs and Sandhoff mice reported a decrease in brain ganglioside GM2 levels and an increase in life span (35Platt F.M. Neises G.R. Reinkensmeier G. Townsend M.J. Perry V.H. Proia R.L. Winchester B. Dwek R.A. Butters T.D. Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin.Science. 1997; 276: 428-431Crossref PubMed Scopus (333) Google Scholar). Based on these reports, miglustat was developed as a treatment for Gaucher disease type I (36Elstein D. Hollak C. Aerts J.M. van Weely S. Maas M. Cox T.M. Lachmann R.H. Hrebicek M. Platt F.M. Butters T.D. et al.Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease.J. Inherit. Metab. Dis. 2004; 27: 757-766Crossref PubMed Scopus (207) Google Scholar). Patients treated with miglustat were observed to have reductions in spleen and liver size and improvements in anemia and thrombocytopenia. However, the magnitude of these changes was significantly lower than those observed for ERT (37Cox T.M. Aerts J.M. Andria G. Beck M. Belmatoug N. Bembi B. Chertkoff R. Vom Dahl S. Elstein D. Erikson A. et al.The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement.J. Inherit. Metab. Dis. 2003; 26: 513-526Crossref PubMed Scopus (209) Google Scholar). In addition, the profile of untoward effects was significant (38Hollak C.E. Hughes D. van Schaik I.N. Schwierin B. Bembi B. Miglustat (Zavesca) in type 1 Gaucher disease: 5-year results of a post-authorisation safety surveillance programme.Pharmacoepidemiol. Drug Saf. 2009; 18: 770-777Crossref PubMed Scopus (69) Google Scholar). Diarrhea, weight loss, and tremor were present in a high percentage of study subjects. The gastrointestinal effects are likely due to the "off target" inhibition of disaccharidases by miglustat. While miglustat is approved for the treatment of Gaucher disease type 1, due to the significant number and severity of these adverse events, its use is limited to those patients in whom ERT is not an option. Several recent studies have raised additional questions regarding the actual mechanism of action of miglustat in the treatment of Gaucher disease and other sphingolipidoses. For example, the effects of miglustat may be due to its modest effects as a glucosylceramide synthase inhibitor or rather be the result of chaperone effects resulting from its direct binding to GBA (39Abian O. Alfonso P. Velazquez-Campoy A. Giraldo P. Pocovi M. Sancho J. Therapeutic strategies for Gaucher disease: miglustat (NB-DNJ) as a pharmacological chaperone for glucocerebrosidase and the different thermostability of velaglucerase alfa and imiglucerase.Mol. Pharm. 2011; 8: 2390-2397Crossref PubMed Scopus (40) Google Scholar). Miglustat cocrystallizes with lysosomal glucocerebrosidase and its binding is greater at neutral compared with acidic pH (40Brumshtein B. Greenblatt H.M. Butters T.D. Shaaltiel Y. Aviezer D. Silman I. Futerman A.H. Sussman J.L. Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid beta-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease.J. Biol. Chem. 2007; 282: 29052-29058Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). The adamantyl analog of miglustat, N-(5-adamantane-1-yl-methoxypentyl) deoxynojirimycin, is significantly more active as a glucosylceramide synthase inhibitor (IC50 150 nM) and retains the ability to penetrate the blood-brain barrier (41Wennekes T. van den Berg R.J. Donker W. van der Marel G.A. Strijland A. Aerts J.M. Overkleeft H.S. Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man.J. Org. Chem. 2007; 72: 1088-1097Crossref PubMed Scopus (123) Google Scholar). However, when the adamantyl compound and miglustat were studied in CNS-based models of glycosphingolipidoses, brain glucosylceramide levels increased markedly (42Ashe K.M. Bangari D. Li L. Cabrera-Salazar M.A. Bercury S.D. Nietupski J.B. Cooper C.G. Aerts J.M. Lee E.R. Copeland D.P. et al.Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.PLoS ONE. 2011; 6: e21758Crossref PubMed Scopus (53) Google Scholar). Ganglioside levels were unchanged. The basis for these observations may be the inhibition of GBA2 by miglustat (33Ridley C.M. Thur K.E. Shanahan J. Thillaiappan N.B. Shen A. Uhl K. Walden C.M. Rahim A.A. Waddington S.N. Platt F.M. et al.β-Glucosidase 2 (GBA2) activity and imino sugar pharmacology.J. Biol. Chem. 2013; 288: 26052-26066Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Miglustat is 60 times more potent as an inhibitor of this enzyme than of glucosylceramide synthase. Recent work has suggested GBA2 as a potential modifier for Gaucher disease (43Yildiz Y. Hoffmann P. Vom Dahl S. Breiden B. Sandhoff R. Niederau C. Horwitz M. Karlsson S. Filocamo M. Elstein D. et al.Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease.Orphanet J. Rare Dis. 2013; 8: 151Crossref PubMed Scopus (24) Google Scholar), and the GBA2 gene is known to be mutated in hereditary spastic paraplegia and cerebellar ataxia (44Hammer M.B. Eleuch-Fayache G. Schottlaender L.V. Nehdi H. Gibbs J.R. Arepalli S.K. Chong S.B. Hernandez D.G. Sailer A. Liu G. et al.Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity.Am. J. Hum. Genet. 2013; 92: 245-251Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 45Martin E. Schule R. Smets K. Rastetter A. Boukhris A. Loureiro J.L. Gonzalez M.A. Mundwiller E. Deconinck T. Wessner
Referência(s)