Нейронопатические мукополисахаридозы: патогенез и будущее терапевтических подходов

Мукополисахаридозы — группа наследственных заболеваний обмена веществ, относящихся к лизосомным болезням накопления и связанных с дефицитом ферментов, расщепляющих гликозаминогликаны (мукополисахариды). Для тяжелых форм мукополисахаридозов I, II и VII типа и мукополисахаридоза III типа характерно первичное поражение центральной нервной системы и нейродегенеративный характер течения заболевания, проявляющийся регрессом когнитивных функций, нарушениями поведения и уменьшением продолжительности жизни. Нейропатогенез мукополисахаридозов изучен недостаточно. Вопрос о возможности обратного развития повреждений на клеточном уровне остается открытым. Эффективных методов лечения мукополисахаридозов с первичным поражением центральной нервной системы до настоящего времени не разработано. Препараты для ферментозаместительной терапии, вводимые внутривенно, не проникают через гематоэнцефалический барьер и, соответственно, не оказывают влияния на течение нейродегенеративного процесса. Многообещающие результаты демонстрируют доклинические исследования высокодозной, интратекальной и интравентрикулярной ферментозаместительной терапии; применения модифицированного фермента, способного преодолевать гематоэнцефалический барьер; генной, клеточной, субстратредуцирующей терапии; методов считывания через стоп-кодон.

1. Neufeld E., Muenzer J. The mucopolysaccharidosis. In: The Metabolic and Molecular Basis of Inherited Disease. C. R. Scriver, A. L. Beaudet, W. S. Sly, D. Valle (eds.). New York: McGraw-Hill. 2001. P. 3421–3452.

2. Lyon G., Kolodny E. H., Pastores G. M. Neurology of Hereditary Metabolic Disease of Children, Third Edition. McGraw-Hill. 2006. 542 p.

3. Wilkinson F. L., Holley R. J., Langford-Smith K. J., Badrinath S., Liao A., Langford-Smith A., Cooper J. D., Jones S. A., Wraith J. E., Wynn R. F., Merry C. L., Bigger B. W. Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB. PLoS One. 2012; 7 (4): 35787.

4. Giugliani R., Federhen A., Silva A. A., Bittar C. M., de Souza C. F., Netto C. B., Mayer F. Q., Baldo G., Matte U. Emerging treatment options for the mucopolysaccharidoses. Res. Rep. Endocr. Dis. 2012; 2: 53–64.

5. Краснопольская К. Д. Наследственные болезни обмена веществ. Справочное пособие для врачей. М.: Фохат. 2005. 364 с.

6. Al Sawaf S., Mayatepek E., Hoffmann B. Neurological findings in Hunter disease: pathology and possible therapeutic effects reviewed. J. Inherit. Metab. Dis. 2008; 31 (4): 473–480.

7. Zafeiriou D. I., Batzios S. P. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. Am. J. Neuroradiol. 2013; 34 (1): 5–13.

8. Arfi A., Richard M., Scherman D. Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease. 2012. URL: http://www.intechopen.com/books/latest-findings-in-intellectual-and-developmental-disabilitiesresearch/innovative-therapeutic-approaches-for-improving-patientlife-condition-with-a-neurological-lysosomal (Available: 25.03.2015).

9. Mehta A., Winchester B. Lysosomal Storage Disease: A Practical Guide. NY: Wiley-Blackwell. 2012. 198 p.

10. Barranger J. A., Cabrera-Salazar M. A. Lysosomal Storage Disorders. Berlin: Springer. 2007. 564 p.

11. Arfi A., Richard M., Gandolphe C., Bonnefont-Rousselot D., Therond P., Scherman D. Neuroinflammatory and oxidative stress phenomena in MPS IIIA mouse model: the positive effect of longterm aspirin treatment. Mol. Genet. Metab. 2011; 103 (1): 18–25.

12. McGlynn R., Dobrenis K., Walkley S. U. Differential subcellular localization of cholesterol, gangliosides, and glycosaminoglycans in murine models of mucopolysaccharide storage disorders. J. Comp. Neurol. 2004; 480 (4): 415–426.

13. Kniesel U., Wolburg H. Tight junctions of the blood-brain barrier. Cell. Mol. Neurobiol. 2000; 20 (1): 57–76.

14. Wilhelm I., Fazakas C., Krizbai I. A. In vitro models of the bloodbrain barrier. Acta Neurobiol. Exp. (Wars). 2011; 71 (1): 113–128.

15. Garbuzova-Davis S., Mirtyl S., Sallot S. A., Hernandez-Ontiveros D. G., Haller E., Sanberg P. R. Blood-brain barrier impairment in MPS III patients. BMC Neurol. 2013; 13: 174.

16. Valstar M. J., Marchal J. P., Grootenhuis M., Colland V., Wijburg F. A. Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome). Orphanet J. Rare Dis. 2011; 6: 43.

17. Blobel G. Christian de Duve (1917–2013). Biologist who won a Nobel prize for insights into cell structure. Nature. 2013; 498: 300.

18. Намазова-Баранова Л. С., Геворкян А. К., Кузенкова Л. М., Кар ка шадзе Г. А., Вашакмадзе Н. Д., Подклетнова Т. В. Ферментозаместительная терапия у детей с мукополисахаридозами в России: особенности организации, внедрение, перспективы. Фарматека. 2013; 11: 45–50.

19. Ou L., Herzog T., Koniar B. L., Gunther R., Whitley C. B. Highdose enzyme replacement therapy in murine Hurler syndrome. Mol. Genet. Metab. 2014; 111 (2): 116–122.

20. Ahn S. Y., Chang Y. S., Sung D. K., Ko A. R., Kim C. H., Yoo D. K., Lim K. H., Sohn Y. B., Jin D. K., Park W. S. High-dose enzyme replacement therapy attenuates cerebroventriculomegaly in a mouse model of mucopolysaccharidosis type II. J. Hum. Genet. 2013; 58 (11): 728–733.

21. Kan S. H., Aoyagi-Scharber M., Le SQ., Vincelette J., Ohmi K., Bullens S., Wendt D. J., Christianson T. M., Tiger P. M., Brown J. R., Lawrence R., Yip B. K., Holtzinger J., Bagri A., Crippen-Harmon D., Vondrak K. N., Chen Z., Hague C. M., Woloszynek J. C., Cheung D. S., Webster K. A., Adintori E. G., Lo M. J., Wong W., Fitzpatrick P. A., LeBowitz J. H., Crawford B. E., Bunting S., Dickson P. I., Neufeld E. F. Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB. Proc. Natl. Acad. Sci. USA. 2014; 111 (41): 14870–14875.

22. Vite C. H., Wang P., Patel R. T., Walton R. M., Walkley S. U., Sellers R. S., Ellinwood N. M., Cheng A. S., White J. T., O'Neill C. A., Haskins M. Biodistribution and pharmacodynamics of recombinant human alpha-L-iduronidase (rhIDU) in mucopolysaccharidosis type I-affected cats following multiple intrathecal administrations. Mol. Genet. Metab. 2011; 103 (3): 268–274.

23. Sohn Y. B., Lee J., Cho S. Y., Kim S. J., Ko A. R., Nam M. H., Jin D. K. Improvement of CNS defects via continuous intrathecal enzyme replacement by osmotic pump in mucopolysaccharidosis type II mice. Am. J. Med. Genet. A. 2013; 161A (5): 1036–1043.

24. Munoz-Rojas M. V., Vieira T., Costa R., Fagondes S., John A., Jardim L. B., Vedolin L. M., Raymundo M., Dickson P. I., Kakkis E., Giugliani R. Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am. J. Med. Genet. A. 2008; 146 A (19): 2538–2544.

25. Munoz-Rojas M. V., Horovitz D. D., Jardim L. B., Raymundo M., Llerena J. C. (Jr.), de Magalhaes Tde S., Vieira T. A., Costa R., Kakkis E., Giugliani R. Intrathecal administration of recombinant human N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. Mol. Genet. Metab. 2010; 99 (4): 346–350.

26. Dickson P. I., Hanson S., McEntee M. F., Vite C. H., Vogler C. A., Mlikotic A., Chen A. H., Ponder K. P., Haskins M. E., Tippin B. L., Le S. Q., Passage M. B., Guerra C., Dierenfeld A., Jens J., Snella E., Kan S. H., Ellinwood N. M. Early versus late treatment of spinal cord compression with long-term intrathecal enzyme replacement therapy in canine mucopolysaccharidosis type I. Mol. Genet. Metab. 2010; 101 (2–3): 115–122.

27. Delgadillo V., O'Callaghan Mdel M., Artuch R., Montero R., Pineda M. Genistein supplementation in patients affected by Sanfilippo disease. J. Inherit. Metab. Dis. 2011; 34 (5): 1039–1044.

28. Vera M., Le S., Kan S. H., Garban H., Naylor D., Mlikotic A., Kaitila I., Harmatz P., Chen A., Dickson P. Immune response to intrathecal enzyme replacement therapy in mucopolysaccharidosis I patients. Pediatr. Res. 2013; 74 (6): 712–720.

29. ClinicalTrials.gov. A service of the U. S. National Institutes of Health. URL: https://clinicaltrials.gov (Available: 24.05.2015).

30. Muenzer J., Hendriksz C. J., Fan Z., Vijayaraghavan S., Perry V., Santra S., Solanki G. A., Mascelli M. A., Pan L., Wang N., Sciarappa K., Barbier A. J. A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. Genet Med. 2015. Epub ahead of print. URL: http://www.ncbi.nlm.nih.gov/pubmed/25834948 (Available: 24.06.2015).

31. Lu J. Z., Boado R. J., Hui E. K., Zhou Q. H., Pardridge W. M. Expression in CHO cells and pharmacokinetics and brain uptake in the Rhesus monkey of an IgG-iduronate-2-sulfatase fusion protein. Biotechnol. Bioeng. 2011; 108 (8): 1954–1964.

32. Boado R. J., Lu J. Z., Hui E. K., Pardridge W. M. Insulin receptor antibody-sulfamidase fusion protein penetrates the primate bloodbrain barrier and reduces glycosoaminoglycans in Sanfilippo type A cells. Mol. Pharm. 2014; 11 (8): 2928–2934.

33. Valstar M. J., Ruijter G. J., van Diggelen O. P., Poorthuis B. J., Wijburg F. A. Sanfilippo syndrome: a mini-review. J. Inherit. Metab. Dis. 2008; 31 (2): 240–252.

34. Saudubray J., van den Berghe J., Walter J. H. Inborn Metabolic Diseases, 5th Edn. Berlin: Springer. 2012. 660 p.

35. Annibali R., Caponi L., Morganti A., Manna M., Gabrielli O., Ficcadenti A. Hunter syndrome (Mucopolysaccharidosis type II), severe phenotype: long term follow-up on patients undergone to hematopoietic stem cell transplantation. Minerva Pediatr. 2013; 65 (5): 487–496.

36. Welling L., Marchal J. P., van Hasselt P., van der Ploeg A. T., Wijburg F. A., Boelens J. J. Early Umbilical Cord Blood-Derived Stem Cell Transplantation Does Not Prevent Neurological Deterioration in Mucopolysaccharidosis Type III. JIMD Rep. 2015; 18: 63–68.

37. Quiviger M., Arfi A., Mansard D., Delacotte L., Pastor M., Scherman D., Marie C. High and prolonged sulfamidase secretion by the liver of MPS-IIIA mice following hydrodynamic tail vein delivery of antibiotic-free pFAR4 plasmid vector. Gene Ther. 2014; 21 (12): 1001–1007.

38. Osborn M. J., McElmurry R. T., Lees C. J., DeFeo A. P., Chen Z. Y., Kay M. A., Naldini L., Freeman G., Tolar J., Blazar B. R. Minicircle DNA-based gene therapy coupled with immune modulation permits long-term expression of -L-iduronidase in mice with mucopolysaccharidosis type I. Mol. Ther. 2011; 19 (3): 450–460.

39. Murrey D. A., Naughton B. J., Duncan F. J., Meadows A. S., Ware T. A., Campbell K. J., Bremer W. G., Walker C. M., Goodchild L., Bolon B., La Perle K., Flanigan K. M., McBride K. L., McCarty D.M., Fu H. Feasibility and safety of systemic rAAV9-hNAGLU delivery for treating mucopolysaccharidosis IIIB: toxicology, biodistribution, and immunological assessments in primates. Hum. Gene Ther. Clin. Dev. 2014; 25 (2): 72–84.

40. Di Domenico C., Villani G. R., Di Napoli D., Reyero E. G., Lombardo A., Naldini L., Di Natale P. Gene therapy for a mucopoly saccharidosis type I murine model with lentiviral-IDUA vector. Hum. Gene Ther. 2005; 16 (1): 81–90.

41. McIntyre C., Derrick-Roberts A. L., Byers S., Anson D. S. Correction of murine mucopolysaccharidosis type IIIA central nervous system pathology by intracerebroventricular lentiviral-mediated gene delivery. J. Gene Med. 2014; 16 (11–12): 374–387.

42. Janson C. G., Romanova L. G., Leone P., Nan Z., Belur L., McIvor R. S., Low W. Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus--L-Iduronidase for Hurler Disease. Neurosurgery. 2014; 74 (1): 99–111.

43. Ariza L., Gimenez-Llort L., Cubizolle A., Pages G., Garcia-Lareu B., Serratrice N., Cots D., Thwaite R., Chillon M., Kremer E. J., Bosch A. Central nervous system delivery of helper-dependent canine adenovirus corrects neuropathology and behavior in mucopolysaccharidosis type VII mice. Hum. Gene Ther. 2014; 25 (3): 199–211.

44. Hinderer C., Bell P., Gurda B. L., Wang Q., Louboutin J. P., Zhu Y., Bagel J., O'Donnell P., Sikora T., Ruane T., Wang P., Haskins M. E., Wilson J. M. Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I. Mol. Ther. 2014; 22 (12): 2018–2027.

45. Fu H., Kang L., Jennings J. S., Moy S. S., Perez A., Dirosario J., McCarty D. M., Muenzer J. Significantly increased lifespan and improved behavioral performances by rAAV gene delivery in adult mucopolysaccharidosis IIIB mice. Gene Ther. 2007; 14 (14): 1065–1077.

46. Tardieu M., Zerah M., Husson B., de Bournonville S., Deiva K., Adamsbaum C., Vincent F., Hocquemiller M., Broissand C., Furlan V., Ballabio A., Fraldi A., Crystal R. G., Baugnon T., Roujeau T., Heard J. M., Danos O. 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.

47. Langford-Smith A., Wilkinson F. L., Langford-Smith K. J., Holley R. J., Sergijenko A., Howe S. J., Bennett W. R., Jones S. A., Wraith J., Merry C. L., Wynn R. F., Bigger B. W. Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Mol. Ther. 2012; 20 (8): 1610–1621.

48. Wakabayashi T., Shimada Y., Akiyama K., Higuchi T., Fukuda T., Kobayashi H., Eto Y., Ida H., Ohashi T. Hematopoietic Stem Cell Gene Therapy Corrects Neuropathic Phenotype in Murine Model of Mucopolysaccharidosis Type II. Hum. Gene Ther. 2015; 26 (6): 357–366.

49. Snyder E. Y., Taylor R. M., Wolfe J. H. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature. 1995; 374 (6520): 367–370.

50. Meng X. L., Shen J. S., Ohashi T., Maeda H., Kim S. U., Eto Y. Brain transplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse. J. Neurosci. Res. 2003; 74 (2): 266–277.

51. Fukuhara Y., Li X. K., Kitazawa Y., Inagaki M., Matsuoka K., Kosuga M., Kosaki R., Shimazaki T., Endo H., Umezawa A., Okano H., Takahashi T., Okuyama T. Histopathological and behavioral improvement of murine mucopolysaccharidosis type VII by intracerebral transplantation of neural stem cells. Mol. Ther. 2006; 13 (3): 548–555.

52. De Ruijter J., Valstar M. J., Wijburg F. A. Mucopolysaccharidosis type III (Sanfilippo Syndrome): emerging treatment strategies. Curr. Pharm. Biotechnol. 2011; 12 (6): 923–930.

53. Feldhammer M., Durand S., Pshezhetsky A. V. Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C. PLoS One. 2009; 4 (10): 7434.

54. Keeling K. M., Brooks D. A., Hopwood J. J., Li P., Thompson J. N., Bedwell D. M. Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum. Mol. Genet. 2001; 10 (3): 291–299.

55. Wang D., Belakhov V., Kandasamy J., Baasov T., Li S. C., Li Y. T., Bedwell D. M., Keeling K. M. The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse. Mol. Genet. Metab. 2012; 105 (1): 116–125.

56. Gunn G., Dai Y., Du M., Belakhov V., Kandasamy J., Schoeb T. R., Baasov T., Bedwell D. M., Keeling K. M. Long-term nonsense suppres sion therapy moderates MPS I-H disease progression. Mol. Genet. Metab. 2014 Mar; 111 (3): 374–81.

57. Friso A., Tomanin R., Salvalaio M., Scarpa M. Genistein reduces glycosaminoglycan levels in a mouse model of mucopolysaccharidosis type II. Brit. J. Pharmacol. 2010; 159 (5): 1082–1091

58. Piotrowska E., Jakobkiewicz-Banecka J., Maryniak A., Tylki- Szymanska A., Puk E., Liberek A., Wegrzyn A., Czartoryska B., Slominska-Wojewodzka M., Wegrzyn G. Two-year follow-up of Sanfilippo Disease patients treated with a genistein-rich isoflavone extract: assessment of effects on cognitive functions and general status of patients. Med. Sci. Monit. 2011; 17 (4): 196–202.

59. Jurecka A., Tylki-Szymanska A. Gynecomastia in MPS IIIA boys: related to treatment or precocious puberty? Mol. Genet. Metab. 2014; 111 (2): 61–62.

60. Kingma S. D., Wagemans T., IJlst L., Wijburg F. A., van Vlies N. Genistein increases glycosaminoglycan levels in mucopoly saccharidosis type I cell models. J. Inherit. Metab. Dis. 2014; 37 (5): 813–821.

61. Kingma S. D., Wagemans T., IJlst L., Seppen J., Gijbels M. J., Wijburg F. A., van Vlies N. Adverse Effects of Genistein in a Mucopolysaccharidosis Type I Mouse Model. JIMD Rep. 2015. Epub ahead of print. URL: http://www.ncbi.nlm.nih.gov/ pubmed/25854773 (Available: 24.06.2015).

62. Negretto G. W., Deon M., Burin M., Biancini G. B., Ribas G., Garcia S. C., Goethel G., Fracasso R., Giugliani L., Giugliani R., Vargas C. R. In vitro effect of genistein on DNA damage in leukocytes from mucopolysaccharidosis IVA patients. Mol. Genet. Metab. 2014; 111 (2): 205–208.