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Open Access 01-02-2018 | Review Article

How close are we to therapies for Sanfilippo disease?

Authors: Lidia Gaffke, Karolina Pierzynowska, Ewa Piotrowska, Grzegorz Węgrzyn

Published in: Metabolic Brain Disease | Issue 1/2018

Abstract

Sanfilippo disease is one of mucopolysaccharidoses (MPS), a group of lysosomal storage diseases characterized by accumulation of partially degraded glycosaminoglycans (GAGs). It is classified as MPS type III, though it is caused by four different genetic defects, determining subtypes A, B, C and D. In each subtype of MPS III, the primary storage GAG is heparan sulfate (HS), but mutations leading to A, B, C, and D subtypes are located in genes coding for heparan N-sulfatase (the SGSH gene), α-N-acetylglucosaminidase (the NAGLU gene), acetyl-CoA:α-glucosaminide acetyltransferase (the HGSNAT gene), and N-acetylglucosamine-6-sulfatase (the GNS gene), respectively. Neurodegenerative changes in the central nervous system (CNS) are major problems in Sanfilippo disease. They cause severe cognitive disabilities and behavioral disturbances. This is the main reason of a current lack of therapeutic options for MPS III patients, while patients from some other MPS types (I, II, IVA, and VI) can be treated with enzyme replacement therapy or bone marrow or hematopoietic stem cell transplantations. Nevertheless, although no therapy is available for Sanfilippo disease now, recent years did bring important breakthroughs in this aspect, and clinical trials are being conducted with enzyme replacement therapy, gene therapy, and substrate reduction therapy. These recent achievements are summarized and discussed in this review.

Aldenhoven M, Jones SA, Bonney D, Borrill RE, Coussons M, Mercer J, Bierings MB, Versluys B, van Hasselt PM, Wijburg FA, van der Ploeg AT, Wynn RF, Boelens JJ (2015) Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines. Biol Blood Marrow Transplant 21:1106–1109. https://doi.org/10.1016/j.bbmt.2015.02.011 CrossRefPubMed

Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML (2015) Sanfilippo syndrome: overall review. Pediatr Int 57:331–338. https://doi.org/10.1111/ped.12636 CrossRefPubMed

Aoyagi-Scharber M, Crippen-Harmon D, Lawrence R, Vincelette J, Yogalingam G, Prill H, Yip BK, Baridon B, Vitelli C, Lee A, Gorostiza O, Adintori EG, Minto WC, Van Vleet JL, Yates B, Rigney S, Christianson TM, Tiger PMN, Lo MJ, Holtzinger J, Fitzpatrick PA, LeBowitz JH, Bullens S, Crawford BE, Bunting S (2017) Clearance of heparan sulfate and attenuation of CNS pathology by intracerebroventricular BMN 250 in Sanfilippo type B mice. Mol Ther Methods Clin Dev 6:43–53. https://doi.org/10.1016/j.omtm.2017.05.009 CrossRefPubMedPubMedCentral

Beard H, Luck AJ, Hassiotis S, King B, Trim PJ, Snel MF, Hopwood JJ, Hemsley KM (2015) Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice. Mol Genet Metab 115:33–40. https://doi.org/10.1016/j.ymgme.2015.03.002 CrossRefPubMed

Boado RJ, Lu JZ, Hui EK, Pardridge WM (2014) Insulin receptor antibody-sulfamidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. Mol Pharm 11:2928–2934. https://doi.org/10.1021/mp500258p CrossRefPubMedPubMedCentral

Boado RJ, Lu JZ, Hui EK, Lin H, Pardridge WM (2016) Insulin receptor antibody-α-N-acetylglucosaminidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo type B fibroblasts. Mol Pharm 13:1385–1392. https://doi.org/10.1021/acs.molpharmaceut.6b00037 CrossRefPubMed

Canals I, Benetó N, Cozar M, Vilageliu L, Grinberg D (2015) EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome. Sci Rep 5:13654. https://doi.org/10.1038/srep13654 CrossRefPubMedPubMedCentral

Dziedzic D, Wegrzyn G, Jakobkiewicz-Banecka J (2010) Impairment of glycosaminoglycan synthesis in mucopolysaccharidosis type IIIA cells by using siRNA: a potential therapeutic approach for Sanfilippo disease. Eur J Hum Genet 18:200–205. https://doi.org/10.1038/ejhg.2009.144 CrossRefPubMed

Fedele AO (2015) Sanfilippo syndrome: causes, consequences, and treatments. Appl Clin Genet 8:269–281. https://doi.org/10.2147/TACG.S57672 CrossRefPubMedPubMedCentral

Fu H, Meadows AS, Ware T, Mohney RP, McCarty DM (2017) Near-complete correction of profound metabolomic impairments corresponding to functional benefit in MPS IIIB mice after IV rAAV9-hNAGLU gene delivery. Mol Ther 25:792–802. https://doi.org/10.1016/j.ymthe.2016.12.025 CrossRefPubMed

Fumić B, Končić MZ, Jug M (2017) Therapeutic potential of hydroxypropyl-β-cyclodextrin-based extract of medicago sativa in the treatment of mucopolysaccharidoses. Planta Med 83:40–50. https://doi.org/10.1055/s-0042-107357 PubMed

Ghosh A, Shapiro E, Rust S, Delaney K, Parker S, Shaywitz AJ, Morte A, Bubb G, Cleary M, Bo T, Lavery C, Bigger BW, Jones SA (2017) Recommendations on clinical trial design for treatment of Mucopolysaccharidosis type III. Orphanet J Rare Dis 12:117. https://doi.org/10.1186/s13023-017-0675-4 CrossRefPubMedPubMedCentral

Gilkes JA, Bloom MD, Heldermon CD (2015) Preferred transduction with AAV8 and AAV9 via thalamic administration in the MPS IIIB model: a comparison of four rAAV serotypes. Mol Genet Metab Rep 6:48–54. https://doi.org/10.1016/j.ymgmr.2015.11.006 CrossRefPubMedPubMedCentral

Gilkes JA, Bloom MD, Heldermon CD (2016) Mucopolysaccharidosis IIIB confers enhanced neonatal intracranial transduction by AAV8 but not by 5, 9 or rh10. Gene Ther 23:263–271. https://doi.org/10.1038/gt.2015.11 CrossRefPubMedPubMedCentral

Giugliani R, Federhen A, Vairo F, Vanzella C, Pasqualim G, da Silva LM, Giugliani L, de Boer AP, de Souza CF, Matte U, Baldo G (2016) Emerging drugs for the treatment of mucopolysaccharidoses. Expert Opin Emerg Drugs 21:9–26. https://doi.org/10.1517/14728214.2016.1123690 CrossRefPubMed

Giugliani R, Nestrasil I, Chen S, Pardridge W, Rioux P (2017) Intravenous infusion of iduronidase-IgG and its impact on the central nervous system in children with Hurler syndrome. Mol Genet Metab 120:S55–S56CrossRef

Gómez-Grau M, Garrido E, Cozar M, Rodriguez-Sureda V, Domínguez C, Arenas C, Gatti RA, Cormand B, Grinberg D, Vilageliu L (2015) Evaluation of aminoglycoside and non-aminoglycoside compounds for stop-codon readthrough therapy in four lysosomal storage diseases. PLoS One 10:e0135873. https://doi.org/10.1371/journal.pone.0135873 CrossRefPubMedPubMedCentral

Heldermon CD, Qin EY, Ohlemiller KK, Herzog ED, Brown JR, Vogler C, Hou W, Orrock JL, Crawford BE, Sands MS (2013) Disease correction by combined neonatal intracranial AAV and systemic lentiviral gene therapy in Sanfilippo syndrome type B mice. Gene Ther 20:913–921. https://doi.org/10.1038/gt.2013.14 CrossRefPubMedPubMedCentral

Jakobkiewicz-Banecka J, Piotrowska E, Narajczyk M, Baranska S, Wegrzyn G (2009) Genistein-mediated inhibition of glycosaminoglycan synthesis, which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growth factor-dependent pathway. J Biomed Sci 16:26. https://doi.org/10.1186/1423-0127-16-26 CrossRefPubMedPubMedCentral

Jakobkiewicz-Banecka J, Gabig-Ciminska M, Kloska A, Malinowska M, Piotrowska E, Banecka-Majkutewicz Z, Banecki B, Wegrzyn A, Wegrzyn G (2016) Glycosaminoglycans and mucopolysaccharidosis type III. Front Biosci (Landmark Ed) 21:1393–1409CrossRef

Jones SA, Breen C, Heap F, Rust S, de Ruijter J, Tump E, Marchal JP, Pan L, Qiu Y, Chung JK, Nair N, Haslett PA, Barbier AJ, Wijburg FA (2016) A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab 118:198–205. https://doi.org/10.1016/j.ymgme.2016.05.006 CrossRefPubMed

Kaidonis X, Liaw WC, Roberts AD, Ly M, Anson D, Byers S (2010) Gene silencing of EXTL2 and EXTL3 as a substrate deprivation therapy for heparan sulphate storing mucopolysaccharidoses. Eur J Hum Genet 18:194–199. https://doi.org/10.1038/ejhg.2009.143 CrossRefPubMed

Kan SH, Troitskaya LA, Sinow CS, Haitz K, Todd AK, Di Stefano A, Le SQ, Dickson PI, Tippin BL (2014) Insulin-like growth factor II peptide fusion enables uptake and lysosomal delivery of α-N-acetylglucosaminidase to mucopolysaccharidosis type IIIB fibroblasts. Biochem J 458:281–289. https://doi.org/10.1042/BJ20130845 CrossRefPubMedPubMedCentral

Kim KH, Dodsworth C, Paras A, Burton BK (2013) High dose genistein aglycone therapy is safe in patients with mucopolysaccharidoses involving the central nervous system. Mol Genet Metab 109:382–385. https://doi.org/10.1016/j.ymgme.2013.06.012 CrossRefPubMed

King B, Marshall N, Beard H, Hassiotis S, Trim PJ, Snel MF, Rozaklis T, Jolly RD, Hopwood JJ, Hemsley KM (2015) Evaluation of enzyme dose and dose-frequency in ameliorating substrate accumulation in MPS IIIA huntaway dog brain. J Inherit Metab Dis 38:341–350. https://doi.org/10.1007/s10545-014-9790-8 CrossRefPubMed

King B, Hassiotis S, Rozaklis T, Beard H, Trim PJ, Snel MF, Hopwood JJ, Hemsley KM (2016a) Low-dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA. J Neurochem 137:409–422. https://doi.org/10.1111/jnc.13533 CrossRefPubMed

King B, Setford ML, Hassiotis S, Trim PJ, Duplock S, Tucker JN, Hattersley K, Snel MF, Hopwood JJ, Hemsley KM (2016b) Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder. Exp Neurol 278:11–21. https://doi.org/10.1016/j.expneurol.2015.11.013 CrossRefPubMed

Kingma SD, Wagemans T, L IJ, Seppen J, Gijbels MJ, Wijburg FA, van Vlies N (2015) Adverse effects of genistein in a mucopolysaccharidosis type I mouse model. JIMD Rep 23:77–83. https://doi.org/10.1007/8904_2015_432 CrossRefPubMedPubMedCentral

Lau AA, Hemsley KM (2017) Adeno-associated viral gene therapy for mucopolysaccharidoses exhibiting neurodegeneration. J Mol Med (in press). https://doi.org/10.1007/s00109-017-1562-0

Malinowska M, Wilkinson FL, Bennett W, Langford-Smith KJ, O'Leary HA, Jakobkiewicz-Banecka J, Wynn R, Wraith JE, Wegrzyn G, Bigger BW (2009) Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice. Mol Genet Metab 98:235–342. https://doi.org/10.1016/j.ymgme.2009.06.013 CrossRefPubMed

Malinowska M, Wilkinson FL, Langford-Smith KJ, Langford-Smith A, Brown JR, Crawford BE, Vanier MT, Grynkiewicz G, Wynn RF, Wraith JE, Wegrzyn G, Bigger BW (2010) Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. PLoS One 5:e14192. https://doi.org/10.1371/journal.pone.0014192 CrossRefPubMedPubMedCentral

Matalonga L, Arias A, Coll MJ, Garcia-Villoria J, Gort L, Ribes A (2014) Treatment effect of coenzyme Q(10) and an antioxidant cocktail in fibroblasts of patients with Sanfilippo disease. J Inherit Metab Dis 37:439–446. https://doi.org/10.1007/s10545-013-9668-1 CrossRefPubMed

Matos L, Canals I, Dridi L, Choi Y, Prata MJ, Jordan P, Desviat LR, Pérez B, Pshezhetsky AV, Grinberg D, Alves S, Vilageliu L (2014) Therapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutations. Orphanet J Rare Dis 9:180. https://doi.org/10.1186/s13023-014-0180-y CrossRefPubMedPubMedCentral

McIntyre C, Derrick-Roberts AL, Byers S, Anson DS (2014) Correction of murine mucopolysaccharidosis type IIIA central nervous system pathology by intracerebroventricular lentiviral-mediated gene delivery. J Gene Med 16:374–387. https://doi.org/10.1002/jgm.2816 CrossRefPubMed

Meadows AS, Duncan FJ, Camboni M, Waligura K, Montgomery C, Zaraspe K, Naughton BJ, Bremer WG, Shilling C, Walker CM, Bolon B, Flanigan KM, McBride KL, McCarty DM, Fu H (2015) A GLP-compliant toxicology and biodistribution study: systemic delivery of an rAAV9 vector for the treatment of mucopolysaccharidosis IIIB. Hum Gene Ther Clin Dev 26:228–242. https://doi.org/10.1089/humc.2015.132 CrossRefPubMedPubMedCentral

Murrey DA, Naughton BJ, Duncan FJ, Meadows AS, Ware TA, Campbell KJ, Bremer WG, Walker CM, Goodchild L, Bolon B, La Perle K, Flanigan KM, McBride KL, McCarty DM, Fu H (2014) Feasibility and safety of systemic rAAV9-hNAGLU delivery for treating mucopolysaccharidosis IIIB: toxicology, biodistribution, and immunological assessments in primates. Hum Gene Ther Clin Dev 25:72–84. https://doi.org/10.1089/humc.2013.208 CrossRefPubMedPubMedCentral

Piotrowska E, Jakobkiewicz-Banecka J, Baranska S, Tylki-Szymanska A, Czartoryska B, Wegrzyn A, Wegrzyn G (2006) Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur J Hum Genet 14:846–852. https://doi.org/10.1038/sj.ejhg.5201623 CrossRefPubMed

Ribera A, Haurigot V, Garcia M, Marcó S, Motas S, Villacampa P, Maggioni L, León X, Molas M, Sánchez V, Muñoz S, Leborgne C, Moll X, Pumarola M, Mingozzi F, Ruberte J, Añor S, Bosch F (2015) Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy. Hum Mol Genet 24:2078–2095. https://doi.org/10.1093/hmg/ddu727 CrossRefPubMed

Roca C, Motas S, Marcó S, Ribera A, Sánchez V, Sánchez X, Bertolin J, León X, Pérez J, Garcia M, Villacampa P, Ruberte J, Pujol A, Haurigot V, Bosch F (2017) Disease correction by AAV-mediated gene therapy in a new mouse model of mucopolysaccharidosis type IIID. Hum Mol Genet 26:1535–1551. https://doi.org/10.1093/hmg/ddx058 CrossRefPubMed

Sergijenko A, Langford-Smith A, Liao AY, Pickford CE, McDermott J, Nowinski G, Langford-Smith KJ, Merry CL, Jones SA, Wraith JE, Wynn RF, Wilkinson FL, Bigger BW (2013) Myeloid/microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. Mol Ther 21:1938–1949. https://doi.org/10.1038/mt.2013.141 CrossRefPubMedPubMedCentral

Singh P, Sharma S, Rath SK (2014) Genistein induces deleterious effects during its acute exposure in Swiss mice. Biomed Res Int 2014:619617PubMedPubMedCentral

Sorrentino NC, Fraldi A (2016) Brain targeting in MPS-IIIA. Pediatr Endocrinol Rev 13(Suppl 1):630–638PubMed

Tardieu M, Zérah M, Husson B, de Bournonville S, Deiva K, Adamsbaum C, Vincent F, Hocquemiller M, Broissand C, Furlan V, Ballabio A, Fraldi A, Crystal RG, Baugnon T, Roujeau T, Heard JM, Danos O (2014) 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 25:506–516. https://doi.org/10.1089/hum.2013.238 CrossRefPubMed

Tardieu M, Zérah M, Gougeon ML, Ausseil J, de Bournonville S, Husson B, Zafeiriou D, Parenti G, Bourget P, Poirier B, Furlan V, Artaud C, Baugnon T, Roujeau T, Crystal RG, Meyer C, Deiva K, Heard JM (2017) Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol 16:712–720. https://doi.org/10.1016/S1474-4422(17)30169-2 CrossRefPubMed

Valstar MJ, Ruijter GJ, van Diggelen OP, Poorthuis BJ, Wijburg FA (2008) Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 31:240–252. https://doi.org/10.1007/s10545-008-0838-5 CrossRefPubMed

Wegrzyn A (2012) Gene expression-targeted isoflavone therapy. IUBMB Life 64:307–315. https://doi.org/10.1002/iub.1007 CrossRefPubMed

Welling L, Marchal JP, van Hasselt P, van der Ploeg AT, Wijburg FA, Boelens JJ (2015) Early umbilical cord blood-derived stem cell transplantation does not prevent neurological deterioration in mucopolysaccharidosis type III. JIMD Rep 18:63–68. https://doi.org/10.1007/8904_2014_350 CrossRefPubMed

Willing AE, Garbuzova-Davis SN, Zayko O, Derasari HM, Rawls AE, James CR, Mervis RF, Sanberg CD, Kuzmin-Nichols N, Sanberg PR (2014) Repeated administrations of human umbilical cord blood cells improve disease outcomes in a mouse model of Sanfilippo syndrome type III B. Cell Transplant 23:1613–1630. https://doi.org/10.3727/096368914X676916 CrossRefPubMed

Winner LK, Beard H, Hassiotis S, Lau AA, Luck AJ, Hopwood JJ, Hemsley KM (2016) A preclinical study evaluating AAVrh10-based gene therapy for Sanfilippo syndrome. Hum Gene Ther 27:363–375. https://doi.org/10.1089/hum.2015.170 CrossRefPubMed

Title: How close are we to therapies for Sanfilippo disease?
Authors: Lidia Gaffke
Karolina Pierzynowska
Ewa Piotrowska
Grzegorz Węgrzyn
Publication date: 01-02-2018
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 1/2018
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-017-0111-4

At a glance: The STEP trials

Springer Medicine

How close are we to therapies for Sanfilippo disease?

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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