Download PDF
Journal of Pediatric Biochemistry 2016; 06(01): 030-038
DOI: 10.1055/s-0036-1582224
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Pathobiological Insights into the Newly Targeted Therapies of Lysosomal Storage Disorders

Simona Sestito
1   Department of Medical and Surgical Sciences, Pediatric Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy
,
Ferdinando Ceravolo
1   Department of Medical and Surgical Sciences, Pediatric Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy
,
Francesca Falvo
1   Department of Medical and Surgical Sciences, Pediatric Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy
,
Angela Nicoletti
1   Department of Medical and Surgical Sciences, Pediatric Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy
,
Ettore Stefanelli
1   Department of Medical and Surgical Sciences, Pediatric Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy
,
Rosalbina Apa
1   Department of Medical and Surgical Sciences, Pediatric Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy
,
Vincenzo Salpietro
2   Department of Pediatrics, University of Messina, Messina, Italy
3   Institute of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, United Kingdom
,
Agata Polizzi
4   National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
,
Martino Ruggieri
5   Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
,
Daniela Concolino
1   Department of Medical and Surgical Sciences, Pediatric Unit, University Magna Graecia of Catanzaro, Catanzaro, Italy
› Author Affiliations
Further Information

Publication History

07 December 2015

23 January 2016

Publication Date:
26 April 2016 (online)

    Permissions and Reprints

Abstract

Lysosomal storage disorders (LSDs) are a heterogeneous group of inborn errors of metabolism caused by inherited deficiencies of any of the lysosomal functions, leading to the accumulation of undegraded substrates in multiple tissues and organs. Two-third of LSDs involves the central nervous system, thus representing the most common cause of pediatric neurodegenerative diseases. Substantial progress has been made in our understanding of the pathophysiology of LSDs, leading to newly targeted therapeutic options. Enzyme replacement therapy (ERT) is currently available for seven LSDs including Gaucher disease, Fabry disease, Pompe disease, and mucopolysaccharidosis (MPS) I (Hurler disease), II (Hunter disease), IV A (Morquio A), and VI (Maroteaux–Lamy disease). ERT reduces lysosomal storage, thus slowing or sometimes avoiding progressive visceral damage altogether. However, ERT is unable to cross the blood–brain barrier (BBB), thus lacking efficacy on neurological manifestations. In patients with MPS I (Hurler disease) under 2 years of age and in selected patients with other LSD, hematopoietic stem cell transplantation is indicated. To bypass the BBB, other approaches, using small molecules are currently being tested and include substrate reduction therapy, which decreases the amount of substrate (currently available for type 1 Gaucher disease and for Niemann–Pick type C disease) and pharmacological chaperones, which enhance the residual activity of the mutant enzyme.

Keywords

lysosomal storage disorders - enzyme replacement therapy - blood–brain barrier
 

  • References

  • 1 Fletcher JM. Screening for lysosomal storage disorders—a clinical perspective. J Inherit Metab Dis 2006; 29 (2–3) 405-408
    CrossrefPubMedGoogle Scholar
  • 2 Pastores GM, Maegawa GH. Clinical neurogenetics: neuropathic lysosomal storage disorders. Neurol Clin 2013; 31 (4) 1051-1071
    CrossrefPubMedGoogle Scholar
  • 3 Vellodi A. Lysosomal storage disorders. Br J Haematol 2005; 128 (4) 413-431
    CrossrefPubMedGoogle Scholar
  • 4 Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999; 281 (3) 249-254
    CrossrefPubMedGoogle Scholar
  • 5 Vellodi A, Bembi B, de Villemeur TB , et al; Neuronopathic Gaucher Disease Task Force of the European Working Group on Gaucher Disease. Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis 2001; 24 (3) 319-327
    CrossrefPubMedGoogle Scholar
  • 6 Wraith JE. The clinical presentation of lysosomal storage disorders. Acta Neurol Taiwan 2004; 13 (3) 101-106
    PubMedGoogle Scholar
  • 7 Wiseman RL, Powers ET, Buxbaum JN, Kelly JW, Balch WE. An adaptable standard for protein export from the endoplasmic reticulum. Cell 2007; 131 (4) 809-821
    CrossrefPubMedGoogle Scholar
  • 8 Platt FM, Walkley SU. Lysosomal defects and storage. In: Platt FM, Walkley SU, eds. Lysosomal Disorders of the Brain: RecentAdvances in Molecular and Cellular Pathogenesis and Treatment. 1st ed. New York, NY: Oxford University Press; 2004: 32-49
    CrossrefGoogle Scholar
  • 9 Hers HG, Van Hoof F. Lysosomes and Storage Diseases. New York, NY: Academic Press; 1973
    Google Scholar
  • 10 Desnick RJ, Thorpe SR, Fiddler MB. Toward enzyme therapy for lysosomal storage diseases. Physiol Rev 1976; 56 (1) 57-99
    PubMedGoogle Scholar
  • 11 Vitner EB, Platt FM, Futerman AH. Common and uncommon pathogenic cascades in lysosomal storage diseases. J Biol Chem 2010; 285 (27) 20423-20427
    CrossrefPubMedGoogle Scholar
  • 12 Walkley SU. Pathogenic cascades in lysosomal disease-Why so complex?. J Inherit Metab Dis 2009; 32 (2) 181-189
    CrossrefPubMedGoogle Scholar
  • 13 Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science 1968; 162 (3853) 570-572
    CrossrefPubMedGoogle Scholar
  • 14 Cheng SH, Smith AE. Gene therapy progress and prospects: gene therapy of lysosomal storage disorders. Gene Ther 2003; 10 (16) 1275-1281
    CrossrefPubMedGoogle Scholar
  • 15 Sands MS, Davidson BL. Gene therapy for lysosomal storage diseases. Mol Ther 2006; 13 (5) 839-849
    CrossrefPubMedGoogle Scholar
  • 16 Sloniowski SP, Fox JC, Gray SJ. Perspectives in using gene therapy for lysosomal storage diseases. Drugs Future 2013; 38: 635-643
    CrossrefPubMedGoogle Scholar
  • 17 Yew NS, Cheng SH. Gene therapy for lysosomal storage disorders. Pediatr Endocrinol Rev 2013; 11 (Suppl. 01) 99-109
    PubMedGoogle Scholar
  • 18 Prasad VK, Kurtzberg J. Cord blood and bone marrow transplantation in inherited metabolic diseases: scientific basis, current status and future directions. Br J Haematol 2010; 148 (3) 356-372
    CrossrefPubMedGoogle Scholar
  • 19 Prasad VK, Kurtzberg J. Transplant outcomes in mucopolysaccharidoses. Semin Hematol 2010; 47 (1) 59-69
    CrossrefPubMedGoogle Scholar
  • 20 de Ru MH, Boelens JJ, Das AM , et al. Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis 2011; 6: 55
    CrossrefPubMedGoogle Scholar
  • 21 Giugliani R, Herber S, Lapagesse L, de Pinto C, Baldo G. Therapy for mucopolysaccharidosis VI: (Maroteaux-Lamy syndrome) present status and prospects. Pediatr Endocrinol Rev 2014; 12 (Suppl. 01) 152-158
    PubMedGoogle Scholar
  • 22 Escolar ML, Poe MD, Provenzale JM , et al. Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med 2005; 352 (20) 2069-2081
    CrossrefPubMedGoogle Scholar
  • 23 Orchard PJ, Blazar BR, Wagner J, Charnas L, Krivit W, Tolar J. Hematopoietic cell therapy for metabolic disease. J Pediatr 2007; 151 (4) 340-346
    CrossrefPubMedGoogle Scholar
  • 24 Neufeld EF. Enzyme replacement therapy—a brief history. Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, United Kingdom: Oxford PharmaGenesis; 2006
    Google Scholar
  • 25 Vellodi A, Tylki-Szymanska A, Davies EH , et al; European Working Group on Gaucher Disease. Management of neuronopathic Gaucher disease: revised recommendations. J Inherit Metab Dis 2009; 32 (5) 660-664
    CrossrefPubMedGoogle Scholar
  • 26 Altarescu G, Hill S, Wiggs E , et al. The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease. J Pediatr 2001; 138 (4) 539-547
    CrossrefPubMedGoogle Scholar
  • 27 Sechi A, Deroma L, Dardis A , 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
    CrossrefPubMedGoogle Scholar
  • 28 Lidove O, West ML, Pintos-Morell G , et al. Effects of enzyme replacement therapy in Fabry disease—a comprehensive review of the medical literature. Genet Med 2010; 12 (11) 668-679
    CrossrefPubMedGoogle Scholar
  • 29 Feriozzi S, Torras J, Cybulla M, Nicholls K, Sunder-Plassmann G, West M ; FOS Investigators. The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy. Clin J Am Soc Nephrol 2012; 7 (1) 60-69
    CrossrefPubMedGoogle Scholar
  • 30 Kishnani PS, Corzo D, Nicolino M , et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007; 68 (2) 99-109
    CrossrefPubMedGoogle Scholar
  • 31 van der Ploeg AT, Clemens PR, Corzo D , et al. A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med 2010; 362 (15) 1396-1406
    CrossrefPubMedGoogle Scholar
  • 32 Valayannopoulos V, Wijburg FA. Therapy for the mucopolysaccharidoses. Rheumatology (Oxford) 2011; 50 (Suppl. 05) v49-v59
    CrossrefPubMedGoogle Scholar
  • 33 Tomanin R, Zanetti A, D'Avanzo F , et al. Clinical efficacy of enzyme replacement therapy in paediatric Hunter patients, an independent study of 3.5 years. Orphanet J Rare Dis 2014; 9: 129
    CrossrefPubMedGoogle Scholar
  • 34 Sestito S, Ceravolo F, Grisolia M, Pascale E, Pensabene L, Concolino D. Profile of idursulfase for the treatment of Hunter syndrome. Res Rep Endoc Disord 2015; 5: 79-90
    PubMedGoogle Scholar
  • 35 Tomatsu S, Alméciga-Díaz CJ, Barbosa H , et al. Therapies of mucopolysaccharidosis IVA (Morquio A syndrome). Expert Opin Orphan Drugs 2013; 1 (10) 805-818
    PubMedGoogle Scholar
  • 36 Tolar J, Grewal SS, Bjoraker KJ , et al. Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transplant 2008; 41 (6) 531-535
    CrossrefPubMedGoogle Scholar
  • 37 Parenti G, Andria G. Pompe disease: from new views on pathophysiology to innovative therapeutic strategies. Curr Pharm Biotechnol 2011; 12 (6) 902-915
    CrossrefPubMedGoogle Scholar
  • 38 Anson DS, McIntyre C, Byers S. Therapies for neurological disease in the mucopolysaccharidoses. Curr Gene Ther 2011; 11 (2) 132-143
    CrossrefPubMedGoogle Scholar
  • 39 Munoz-Rojas MV, Vieira T, Costa R , et al. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J Med Genet A 2008; 146A (19) 2538-2544
    CrossrefPubMedGoogle Scholar
  • 40 Giraldo P, Alfonso P, Atutxa K , et al. Real-world clinical experience with long-term miglustat maintenance therapy in type 1 Gaucher disease: the ZAGAL project. Haematologica 2009; 94 (12) 1771-1775
    CrossrefPubMedGoogle Scholar
  • 41 Hollak CE, Hughes D, van Schaik IN, 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 (9) 770-777
    CrossrefPubMedGoogle Scholar
  • 42 Balwani M, Burrow TA, Charrow J , et al. Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States. Mol Genet Metab 2016; 117 (2) 95-103
    CrossrefPubMedGoogle Scholar
  • 43 Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007; 6 (9) 765-772
    CrossrefPubMedGoogle Scholar
  • 44 Patterson MC, Mengel E, Vanier MT , et al; NPC Registry investigators. Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J Rare Dis 2015; 10: 65
    CrossrefPubMedGoogle Scholar
  • 45 Piotrowska E, Jakóbkiewicz-Banecka J, Barańska S , et al. Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur J Hum Genet 2006; 14 (7) 846-852
    CrossrefPubMedGoogle Scholar
  • 46 de Ruijter J, Valstar MJ, Narajczyk M , et al. Genistein in Sanfilippo disease: a randomized controlled crossover trial. Ann Neurol 2012; 71 (1) 110-120
    CrossrefPubMedGoogle Scholar
  • 47 Malinová V, Węgrzyn G, Narajczyk M. The use of elevated doses of genistein-rich soy extract in the gene expression-targeted isoflavone therapy for Sanfilippo disease patients. JIMD Rep 2012; 5: 21-25
    PubMedGoogle Scholar
  • 48 Ashe KM, Bangari D, Li L , et al. Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease. PLoS ONE 2011; 6 (6) e21758
    CrossrefPubMedGoogle Scholar
  • 49 Ashe KM, Budman E, Bangari DS , et al. Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease. Mol Med 2015; 21: 389-399
    PubMedGoogle Scholar
  • 50 Douillard-Guilloux G, Raben N, Takikita S , et al. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum Mol Genet 2010; 19 (4) 684-696
    CrossrefPubMedGoogle Scholar
  • 51 Fan JQ, Ishii S, Asano N, Suzuki Y. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 1999; 5 (1) 112-115
    CrossrefPubMedGoogle Scholar
  • 52 Germain DP, Fan JQ. Pharmacological chaperone therapy by active-site-specific chaperones in: Fabry disease: in vitro and preclinical studies. Int J Clin Pharmacol Ther 2009; 47 (Suppl. 01) S111-S117
    CrossrefPubMedGoogle Scholar
  • 53 Valenzano KJ, Khanna R, Powe AC , et al. Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders. Assay Drug Dev Technol 2011; 9 (3) 213-235
    CrossrefPubMedGoogle Scholar
  • 54 Sawkar AR, Adamski-Werner SL, Cheng WC , et al. Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles. Chem Biol 2005; 12 (11) 1235-1244
    CrossrefPubMedGoogle Scholar
  • 55 Parenti G, Zuppaldi A, Gabriela Pittis M , et al. Pharmacological enhancement of mutated alpha-glucosidase activity in fibroblasts from patients with Pompe disease. Mol Ther 2007; 15 (3) 508-514
    CrossrefPubMedGoogle Scholar
  • 56 Suzuki Y, Ichinomiya S, Kurosawa M , et al. Therapeutic chaperone effect of N-octyl 4-epi-β-valienamine on murine G(M1)-gangliosidosis. Mol Genet Metab 2012; 106 (1) 92-98
    CrossrefPubMedGoogle Scholar
  • 57 Benjamin ER, Khanna R, Schilling A , et al. Co-administration with the pharmacological chaperone AT1001 increases recombinant human α-galactosidase A tissue uptake and improves substrate reduction in Fabry mice. Mol Ther 2012; 20 (4) 717-726
    CrossrefPubMedGoogle Scholar
  • 58 Khanna R, Flanagan JJ, Feng J , et al. The pharmacological chaperone AT2220 increases recombinant human acid α-glucosidase uptake and glycogen reduction in a mouse model of Pompe disease. PLoS ONE 2012; 7 (7) e40776
    CrossrefPubMedGoogle Scholar
  • 59 Rastall DP, Amalfitano A. Recent advances in gene therapy for lysosomal storage disorders. Appl Clin Genet 2015; 8: 157-169
    PubMedGoogle Scholar
  • 60 Worgall S, Sondhi D, Hackett NR , et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 2008; 19 (5) 463-474
    CrossrefPubMedGoogle Scholar
  • 61 McPhee SW, Janson CG, Li C , et al. Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 2006; 8 (5) 577-588
    CrossrefPubMedGoogle Scholar
  • 62 Tardieu M, Zérah M, Husson B , et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum Gene Ther 2014; 25 (6) 506-516
    CrossrefPubMedGoogle Scholar
  • 63 Biffi A, Montini E, Lorioli L , et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013; 341 (6148) 1233158
    CrossrefPubMedGoogle Scholar
  • 64 Parenti G, Andria G, Ballabio A. Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med 2015; 66: 471-486
    CrossrefPubMedGoogle Scholar
  • 65 Raben N, Schreiner C, Baum R , et al. Suppression of autophagy permits successful enzyme replacement therapy in a lysosomal storage disorder—murine Pompe disease. Autophagy 2010; 6 (8) 1078-1089
    CrossrefPubMedGoogle Scholar
  • 66 Sarkar C, Zhang Z, Mukherjee AB. Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from INCL patients. Mol Genet Metab 2011; 104 (3) 338-345
    CrossrefPubMedGoogle Scholar
  • 67 Sardiello M, Palmieri M, di Ronza A , et al. A gene network regulating lysosomal biogenesis and function. Science 2009; 325 (5939) 473-477
    PubMedGoogle Scholar