Effect of systemic high dose enzyme replacement therapy on the improvement of CNS defects in a mouse model of mucopolysaccharidosis type II

Orphanet Journal of Rare Diseases

Dong-Kyu Jin²  Sung Won Park⁴  Young Bae Sohn⁵  Sujin Kim³  Min Jung Kwak⁶  Ah-Ra Ko¹  Jeehun Lee²  Sung Yoon Cho² 

[1] Clinical Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea;Department of Pediatrics, Myongji Hospital, Seonam Univeristy College of Medicine, Goyang, Republic of Korea;Department of Pediatrics, Dankook University College of Medicine, Cheil General Hospital & Woman’s Health Care Center, Seoul, Republic of Korea;Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea;Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea

关键词: Hunterase®;    Iduronate-2-sulfatase;    Enzyme replacement therapy;    Central nervous system;    Hunter syndrome;    Mucopolysaccharidosis type II;   

Others  :  1230397
DOI  :  10.1186/s13023-015-0356-0

 received in 2015-07-08, accepted in 2015-10-16,  发布年份 2015

【 摘 要 】

Background

Mucopolysaccharidosis type II (MPS II, Hunter syndrome), is caused by a deficiency of iduronate-2-sulfatase (IDS). Despite the therapeutic effect of intravenous enzyme replacement therapy (ERT), the central nervous system (CNS) defects persist because the enzyme cannot cross the blood-brain barrier (BBB). There have been several trials of direct infusion to the cerebrospinal space showing promising results; however, this approach may have limitations in clinical situations such as CNS infection. The objective of this study was to improve the CNS defect with systemic high-dose ERT.

Methods

Systemic ERT was performed using three doses (1, 5, and 10 mg/kg weekly) of IDS for three different durations (1, 3, and 6 months) in IDS knock out (KO) mice of two age groups (2 months, 8 months). GAG measurement in tissues, brain pathology, and behavioral assessment were analyzed.

Results

Brain IDS activities increased in parallel with the concentrations of IDS injected. The glycosaminoglycan (GAG) level and histopathology in the brains of the young mice improved in a dose- and duration-dependent manner; however, those were not improved in the old mice, even at higher doses of IDS. The spontaneous alternation behavior was recovered in young KO mice treated with ≥ 5 mg/kg IDS; however, no significant improvement was observed in old KO mice.

Conclusions

These results suggest that high-dose ERT given to mice of earlier ages may play a role in preventing GAG accumulation and preventing CNS damage in IDS KO mice. Therefore, ERT above the present standard dose, starting in early childhood, could be a promising treatment regimen for reducing neurological impairment in Hunter syndrome.

【 授权许可】

   
2015 Cho et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999; 281:249-54.
• [2]Cho SY, Sohn YB, Jin DK. An overview of Korean patients with mucopolysaccharidosis and collaboration through the Asia Pacific MPS Network. Intractable Rare Dis Res. 2014; 3:79-86.
• [3]Wraith JE, Beck M, Lane R, van der Ploeg A, Shapiro E, Xue Y, Kakkis ED, Guffon N. Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase). Pediatrics. 2007; 120:e37-46.
• [4]Clarke LA, Wraith JE, Beck M, Kolodny EH, Pastores GM, Muenzer J, Rapoport DM, Berger KI, Sidman M, Kakkis ED et al.. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009; 123:229-40.
• [5]Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng CM, Vellodi A, Martin R, Ramaswami U, Gucsavas-Calikoglu M et al.. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006; 8:465-73.
• [6]Muenzer J, Beck M, Eng CM, Giugliani R, Harmatz P, Martin R, Ramaswami U, Vellodi A, Wraith JE, Cleary M et al.. Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome. Genet Med. 2011; 13:95-101.
• [7]Muenzer J, Beck M, Giugliani R, Suzuki Y, Tylki-Szymanska A, Valayannopoulos V, Vellodi A, Wraith JE. Idursulfase treatment of Hunter syndrome in children younger than 6 years: results from the Hunter Outcome Survey. Genet Med. 2011; 13:102-9.
• [8]Jung SC, Park ES, Choi EN, Kim CH, Kim SJ, Jin DK. Characterization of a novel mucopolysaccharidosis type II mouse model and recombinant AAV2/8 vector-mediated gene therapy. Mol Cells. 2010; 30:13-8.
• [9]Polito VA, Abbondante S, Polishchuk RS, Nusco E, Salvia R, Cosma MP. Correction of CNS defects in the MPSII mouse model via systemic enzyme replacement therapy. Hum Mol Genet. 2010; 19:4871-85.
• [10]Ahn SY, Chang YS, Sung DK, Ko AR, Kim CH, Yoo DK, Lim KH, Sohn YB, Jin DK, Park WS. High-dose enzyme replacement therapy attenuates cerebroventriculomegaly in a mouse model of mucopolysaccharidosis type II. J Hum Genet. 2013; 58:728-33.
• [11]Sohn YB, Cho SY, Park SW, Kim SJ, Ko AR, Kwon EK, Han SJ, Jin DK. Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome). Orphanet J Rare Dis. 2013; 8:42. BioMed Central Full Text
• [12]Vorbrodt AW, Dobrogowska DH, Tarnawski M. Immunogold study of interendothelial junction-associated and glucose transporter proteins during postnatal maturation of the mouse blood–brain barrier. J Neurocytol. 2001; 30:705-16.
• [13]McCarty DM, DiRosario J, Gulaid K, Muenzer J, Fu H. Mannitol-facilitated CNS entry of rAAV2 vector significantly delayed the neurological disease progression in MPS IIIB mice. Gene Ther. 2009; 16:1340-52.
• [14]Voznyi YV, Keulemans JL, van Diggelen OP. A fluorimetric enzyme assay for the diagnosis of MPS II (Hunter disease). J Inherit Metab Dis. 2001; 24:675-80.
• [15]Cardone M, Polito VA, Pepe S, Mann L, D’Azzo A, Auricchio A, Ballabio A, Cosma MP. Correction of hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery. Hum Mol Genet. 2006; 15:1225-36.
• [16]Higuchi T, Shimizu H, Fukuda T, Kawagoe S, Matsumoto J, Shimada Y, Kobayashi H, Ida H, Ohashi T, Morimoto H et al.. Enzyme Replacement Therapy (ERT) procedure for Mucopolysaccharidosis Type II (MPS II) by Intraventricular Administration (IVA) in murine MPS II. Mol Genet Metab. 2012; 107:122-8.
• [17]Kwon SH, Ma SX, Joo HJ, Lee SY, Jang CG. Inhibitory effects of eucommia ulmoides Oliv. Bark on scopolamine-induced learning and memory deficits in mice. Biomol Ther (Seoul). 2013; 21:462-9.
• [18]Heo HJ, Park YJ, Suh YM, Choi SJ, Kim MJ, Cho HY, Chang YJ, Hong B, Kim HK, Kim E et al.. Effects of oleamide on choline acetyltransferase and cognitive activities. Biosci Biotechnol Biochem. 2003; 67:1284-91.
• [19]Mamiya T, Asanuma T, Kise M, Ito Y, Mizukuchi A, Aoto H, Ukai M. Effects of pre-germinated brown rice on beta-amyloid protein-induced learning and memory deficits in mice. Biol Pharm Bull. 2004; 27:1041-5.
• [20]Sarter M, Bodewitz G, Stephens DN. Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines. Psychopharmacology (Berl). 1988; 94:491-5.
• [21]Baldo G, Mayer FQ, Martinelli BZ, de Carvalho TG, Meyer FS, de Oliveira PG, Meurer L, Tavares A, Matte U, Giugliani R. Enzyme replacement therapy started at birth improves outcome in difficult-to-treat organs in mucopolysaccharidosis I mice. Mol Genet Metab. 2013; 109:33-40.
• [22]Dierenfeld AD, McEntee MF, Vogler CA, Vite CH, Chen AH, Passage M, Le S, Shah S, Jens JK, Snella EM et al.. Replacing the enzyme alpha-L-iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I. Sci Transl Med. 2010; 2:60ra89.
• [23]Vogler C, Levy B, Grubb JH, Galvin N, Tan Y, Kakkis E, Pavloff N, Sly WS. Overcoming the blood–brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A. 2005; 102:14777-82.
• [24]Baldo G, Giugliani R, Matte U. Lysosomal enzymes may cross the blood–brain-barrier by pinocytosis: implications for enzyme replacement therapy. Med Hypotheses. 2014; 82:478-80.
• [25]Banks WA. Are the extracellular [correction of extracelluar] pathways a conduit for the delivery of therapeutics to the brain? Curr Pharm Des. 2004; 10:1365-70.
• [26]Sohn YB, Lee J, Cho SY, Kim SJ, Ko AR, Nam MH, Jin DK. Improvement of CNS defects via continuous intrathecal enzyme replacement by osmotic pump in mucopolysaccharidosis type II mice. Am J Med Genet A. 2013; 161A:1036-43.
• [27]Calias P, Papisov M, Pan J, Savioli N, Belov V, Huang Y, Lotterhand J, Alessandrini M, Liu N, Fischman AJ et al.. CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder. PLoS One. 2012; 7:e30341.
• [28]Polito VA, Cosma MP. IDS crossing of the blood–brain barrier corrects CNS defects in MPSII mice. Am J Hum Genet. 2009; 85:296-301.
• [29]Tanaka A, Okuyama T, Suzuki Y, Sakai N, Takakura H, Sawada T, Tanaka T, Otomo T, Ohashi T, Ishige-Wada M et al.. Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: a nationwide survey in Japan. Mol Genet Metab. 2012; 107:513-20.
• [30]Ou L, Herzog T, Koniar BL, Gunther R, Whitley CB. High-dose enzyme replacement therapy in murine Hurler syndrome. Mol Genet Metab. 2014; 111:116-22.
• [31]Dunder U, Kaartinen V, Valtonen P, Vaananen E, Kosma VM, Heisterkamp N, Groffen J, Mononen I. Enzyme replacement therapy in a mouse model of aspartylglycosaminuria. FASEB J. 2000; 14:361-7.
• [32]Lee WC, Courtenay A, Troendle FJ, Stallings-Mann ML, Dickey CA, DeLucia MW, Dickson DW, Eckman CB. Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy. FASEB J. 2005; 19:1549-51.
• [33]Blanz J, Stroobants S, Lullmann-Rauch R, Morelle W, Ludemann M, D’Hooge R, Reuterwall H, Michalski JC, Fogh J, Andersson C et al.. Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in alpha-mannosidosis mice. Hum Mol Genet. 2008; 17:3437-45.
• [34]Matzner U, Herbst E, Hedayati KK, Lullmann-Rauch R, Wessig C, Schroder S, Eistrup C, Moller C, Fogh J, Gieselmann V. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet. 2005; 14:1139-52.
• [35]Matzner U, Lullmann-Rauch R, Stroobants S, Andersson C, Weigelt C, Eistrup C, Fogh J, D’Hooge R, Gieselmann V. Enzyme replacement improves ataxic gait and central nervous system histopathology in a mouse model of metachromatic leukodystrophy. Mol Ther. 2009; 17:600-6.
• [36]Crawley AC, King B, Berg T, Meikle PJ, Hopwood JJ. Enzyme replacement therapy in alpha-mannosidosis guinea-pigs. Mol Genet Metab. 2006; 89:48-57.
• [37]Rozaklis T, Beard H, Hassiotis S, Garcia AR, Tonini M, Luck A, Pan J, Lamsa JC, Hopwood JJ, Hemsley KM. Impact of high-dose, chemically modified sulfamidase on pathology in a murine model of MPS IIIA. Exp Neurol. 2011; 230:123-30.