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Disease correction by combined neonatal intracranial AAV and systemic lentiviral gene therapy in Sanfilippo Syndrome type B mice

Gene Therapy volume 20, pages 913–921 (2013)Cite this article

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Abstract

Mucopolysaccharidosis type IIIB (MPS IIIB) or Sanfilippo Syndrome type B is a lysosomal storage disease resulting from the deficiency of N-acetyl glucosaminidase (NAGLU) activity. We previously showed that intracranial adeno-associated virus (AAV)-based gene therapy results in partial improvements of several aspects of the disease. In an attempt to further correct the disease, MPS IIIB mice were treated at 2–4 days of age with intracranial AAV2/5-NAGLU (IC-AAV), intravenous lentiviral-NAGLU (IV-LENTI) or the combination of both (BOTH). The BOTH group had the most complete biochemical and histological improvements of any treatment group. Compared with untreated MPS IIIB animals, all treatments resulted in significant improvements in motor function (rotarod) and hearing (auditory-evoked brainstem response). In addition, each treatment group had a significantly increased median life span compared with the untreated group (322 days). The combination arm had the greatest increase (612 days), followed by IC-AAV (463 days) and IV-LENTI (358 days). Finally, the BOTH group had nearly normal circadian rhythm measures with improvement in time to activity onset. In summary, targeting both the systemic and central nervous system disease of MPS IIIB early in life appears to be the most efficacious approach for this inherited metabolic disorder.

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References

  1. Yogalingam G, Hopwood JJ . Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: diagnostic, clinical, and biological implications. Hum Mutat 2001; 18: 264–281.

    Article  CAS  PubMed  Google Scholar 

  2. Weber B, Blanch L, Clements PR, Scott HS, Hopwood JJ . Cloning and expression of the gene involved in Sanfilippo B syndrome (mucopolysaccharidosis III B). Hum Mol Genet 1996; 5: 771–777.

    Article  CAS  PubMed  Google Scholar 

  3. Zhao HG, Li HH, Bach G, Schmidtchen A, Neufeld EF . The molecular basis of Sanfilippo syndrome type B. Proc Natl Acad Sci USA 1996; 93: 6101–6105.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Li HH, Yu WH, Rozengurt N, Zhao HZ, Lyons KM, Anagnostaras S et al. Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase. Proc Natl Acad Sci USA 1999; 96: 14505–14510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Heldermon CD, Hennig AK, Ohlemiller KK, Ogilvie JM, Herzog ED, Breidenbach A et al. Development of sensory, motor and behavioral deficits in the murine model of Sanfilippo syndrome type B. PLoS One 2007; 2: e772.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Fu H, Samulski RJ, McCown TJ, Picornell YJ, Fletcher D, Muenzer J . Neurological correction of lysosomal storage in a mucopolysaccharidosis IIIB mouse model by adeno-associated virus-mediated gene delivery. Mol Ther 2002; 5: 42–49.

    Article  CAS  PubMed  Google Scholar 

  7. Cressant A, Desmaris N, Verot L, Brejot T, Froissart R, Vanier MT et al. Improved behavior and neuropathology in the mouse model of Sanfilippo type IIIB disease after adeno-associated virus-mediated gene transfer in the striatum. J Neurosci 2004; 24: 10229–10239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fu H, Kang L, Jennings JS, Moy SS, Perez A, Dirosario J et al. Significantly increased lifespan and improved behavioral performances by rAAV gene delivery in adult mucopolysaccharidosis IIIB mice. Gene Therapy 2007; 14: 1065–1077.

    Article  CAS  PubMed  Google Scholar 

  9. Di Natale P, Di Domenico C, Gargiulo N, Castaldo S, Gonzalez YRE, Mithbaokar P et al. Treatment of the mouse model of mucopolysaccharidosis type IIIB with lentiviral-NAGLU vector. Biochem J 2005; 388: 639–646.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Fu H, DiRosario J, Kang L, Muenzer J, McCarty DM . Restoration of central nervous system alpha-N-acetylglucosaminidase activity and therapeutic benefits in mucopolysaccharidosis IIIB mice by a single intracisternal recombinant adeno-associated viral type 2 vector delivery. J Gene Med 2010; 12: 624–633.

    Article  CAS  PubMed  Google Scholar 

  11. 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 Therapy 2009; 16: 1340–1352.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Heldermon CD, Ohlemiller KK, Herzog ED, Vogler C, Qin E, Wozniak DF et al. Therapeutic efficacy of bone marrow transplant, intracranial AAV-mediated gene therapy, or both in the mouse model of MPS IIIB. Mol Ther 2010; 18: 873–880.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Ellinwood NM, Ausseil J, Desmaris N, Bigou S, Liu S, Jens JK et al. Safe, efficient, and reproducible gene therapy of the brain in the Dog Models of Sanfilippo and Hurler Syndromes. Mol Ther 2010; 19: 251–259.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Vogler C, Levy B, Grubb JH, Galvin N, Tan Y, Kakkis E et al. Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII. Proc Natl Acad Sci USA 2005; 102: 14777–14782.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Sferra TJ, Backstrom K, Wang C, Rennard R, Miller M, Hu Y . Widespread correction of lysosomal storage following intrahepatic injection of a recombinant adeno-associated virus in the adult MPS VII mouse. Mol Ther 2004; 10: 478–491.

    Article  CAS  PubMed  Google Scholar 

  16. Lin D, Donsante A, Macauley S, Levy B, Vogler C, Sands MS . Central nervous system-directed AAV2/5-mediated gene therapy synergizes with bone marrow transplantation in the murine model of globoid-cell leukodystrophy. Mol Ther 2007; 15: 44–52.

    Article  CAS  PubMed  Google Scholar 

  17. Donsante A, Levy B, Vogler C, Sands MS . Clinical response to persistent, low-level beta-glucuronidase expression in the murine model of mucopolysaccharidosis type VII. J Inherit Metab Dis 2007; 30: 227–238.

    Article  CAS  PubMed  Google Scholar 

  18. Sands MS, Barker JE . Percutaneous intravenous injection in neonatal mice. Lab Anim Sci 1999; 49: 328–330.

    CAS  PubMed  Google Scholar 

  19. Deakin JA, Lyon M . A simplified and sensitive fluorescent method for disaccharide analysis of both heparan sulfate and chondroitin/dermatan sulfates from biological samples. Glycobiology 2008; 18: 483–491.

    Article  CAS  PubMed  Google Scholar 

  20. Lawrence R, Brown JR, Al-Mafraji K, Lamanna WC, Beitel JR, Boons GJ et al. Disease-specific non-reducing end carbohydrate biomarkers for mucopolysaccharidoses. Nat Chem Biol 2012; 8: 197–204.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Lawrence R, Olson SK, Steele RE, Wang L, Warrior R, Cummings RD et al. Evolutionary differences in glycosaminoglycan fine structure detected by quantitative glycan reductive isotope labeling. J Biol Chem 2008; 283: 33674–33684.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Yogalingam G, Weber B, Meehan J, Rogers J, Hopwood JJ . Mucopolysaccharidosis type IIIB: characterisation and expression of wild-type and mutant recombinant alpha-N-acetylglucosaminidase and relationship with sanfilippo phenotype in an attenuated patient. Biochim Biophys Acta 2000; 1502: 415–425.

    Article  CAS  PubMed  Google Scholar 

  23. Colville GA, Watters JP, Yule W, Bax M . Sleep problems in children with Sanfilippo syndrome. Dev Med Child Neurol 1996; 38: 538–544.

    Article  CAS  PubMed  Google Scholar 

  24. Gorlin R . Genetic hearing loss associated with endocrine and metabolic disorders. In: Gorlin RJ, Toriello HV, Cohen MM, (eds). Hereditary Hearing Loss and its Syndromes. Oxford Monographs on Medical Genetics vol. 28. Oxford University Press: New York, 1995, pp 318–354.

    Google Scholar 

  25. Bredenkamp JK, Smith ME, Dudley JP, Williams JC, Crumley RL, Crockett DM . Otolaryngologic manifestations of the mucopolysaccharidoses. Ann Otol Rhinol Laryngol 1992; 101: 472–478.

    Article  CAS  PubMed  Google Scholar 

  26. Leung LS, Weinstein GW, Hobson RR . Further electroretinographic studies of patients with mucopolysaccharidoses. Birth Defects Orig Artic Ser 1971; 7: 32–40.

    CAS  PubMed  Google Scholar 

  27. Yoshimitsu M, Sato T, Tao K, Walia JS, Rasaiah VI, Sleep GT et al. Bioluminescent imaging of a marking transgene and correction of Fabry mice by neonatal injection of recombinant lentiviral vectors. Proc Natl Acad Sci USA 2004; 101: 16909–16914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Biffi A, Bartolomae CC, Cesana D, Cartier N, Aubourg P, Ranzani M et al. Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood 2011; 117: 5332–5339.

    Article  CAS  PubMed  Google Scholar 

  29. Wang GP, Levine BL, Binder GK, Berry CC, Malani N, McGarrity G et al. Analysis of lentiviral vector integration in HIV+ study subjects receiving autologous infusions of gene modified CD4+ T cells. Mol Ther 2009; 17: 844–850.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009; 326: 818–823.

    Article  CAS  PubMed  Google Scholar 

  31. Zheng Y, Ryazantsev S, Ohmi K, Zhao HZ, Rozengurt N, Kohn DB et al. Retrovirally transduced bone marrow has a therapeutic effect on brain in the mouse model of mucopolysaccharidosis IIIB. Mol Genet Metab 2004; 82: 286–295.

    Article  CAS  PubMed  Google Scholar 

  32. Fu H, Dirosario J, Killedar S, Zaraspe K, McCarty DM . Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol Ther 2011; 19: 1025–1033.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL, Clancy JP et al. Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther 2007; 18: 726–732.

    Article  CAS  PubMed  Google Scholar 

  34. Hasbrouck NC, High KA . AAV-mediated gene transfer for the treatment of hemophilia B: problems and prospects. Gene Therapy 2008; 15: 870–875.

    Article  CAS  PubMed  Google Scholar 

  35. Nathwani AC, Rosales C, McIntosh J, Rastegarlari G, Nathwani D, Raj D et al. Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 2011; 19: 876–885.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Li H, Malani N, Hamilton SR, Schlachterman A, Bussadori G, Edmonson SE et al. Assessing the potential for AAV vector genotoxicity in a murine model. Blood 2010; 117: 3311–3319.

    Article  PubMed  Google Scholar 

  37. Reiss J, Hahnewald R . Molybdenum cofactor deficiency: mutations in GPHN, MOCS1, and MOCS2. Hum Mutat 2010; 32: 10–18.

    Article  Google Scholar 

  38. Bell P, Moscioni AD, McCarter RJ, Wu D, Gao G, Hoang A et al. Analysis of tumors arising in male B6C3F1 mice with and without AAV vector delivery to liver. Mol Ther 2006; 14: 34–44.

    Article  CAS  PubMed  Google Scholar 

  39. Embury JE, Frost S, Charron CE, Madrigal E, Perera O, Poirier AE et al. Hepatitis virus protein X-phenylalanine hydroxylase fusion proteins identified in PKU mice treated with AAV-WPRE vectors. Gene Therapy Mol Biol 2008; 12: 69–76.

    CAS  Google Scholar 

  40. Donsante A, Miller DG, Li Y, Vogler C, Brunt EM, Russell DW et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 2007; 317: 477.

    Article  CAS  PubMed  Google Scholar 

  41. Donsante A, Vogler C, Muzyczka N, Crawford JM, Barker J, Flotte T et al. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Therapy 2001; 8: 1343–1346.

    Article  CAS  PubMed  Google Scholar 

  42. Rosas LE, Grieves JL, Zaraspe K, La Perle KM, Fu H, McCarty DM . Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol Ther 2012; 20: 2098–2110.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Hawkins-Salsbury JA, Reddy AS, Sands MS . Combination therapies for lysosomal storage disease: is the whole greater than the sum of its parts? Hum Mol Genet 2011; 20: R54–R60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Biswas S, LeVine SM . Substrate-reduction therapy enhances the benefits of bone marrow transplantation in young mice with globoid cell leukodystrophy. Pediatr Res 2002; 51: 40–47.

    Article  PubMed  Google Scholar 

  45. Biffi A, Capotondo A, Fasano S, del Carro U, Marchesini S, Azuma H et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J Clin Inv 2006; 116: 3070–3082.

    Article  CAS  Google Scholar 

  46. Jeyakumar M, Norflus F, Tifft CJ, Cortina-Borja M, Butters TD, Proia RL et al. Enhanced survival in Sandhoff disease mice receiving a combination of substrate deprivation therapy and bone marrow transplantation. Blood 2001; 97: 327–329.

    Article  CAS  PubMed  Google Scholar 

  47. Lee JP, Jeyakumar M, Gonzalez R, Takahashi H, Lee PJ, Baek RC et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med 2007; 13: 439–447.

    Article  CAS  PubMed  Google Scholar 

  48. Marsh J, Fensom AH . 4-Methylumbelliferyl alpha-N-acetylglucosaminidase activity for diagnosis of Sanfilippo B disease. Clin Genet 1985; 27: 258–262.

    Article  CAS  PubMed  Google Scholar 

  49. Sands MS, Barker JE, Vogler C, Levy B, Gwynn B, Galvin N et al. Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates. Lab Invest 1993; 68: 676–686.

    CAS  PubMed  Google Scholar 

  50. Herzog ED, Aton SJ, Numano R, Sakaki Y, Tei H . Temporal precision in the mammalian circadian system: a reliable clock from less reliable neurons. J Biol Rhythms 2004; 19: 35–46.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was funded in part by NIH grants NS043205 (MSS), HD055461 (MSS), K08 DK085141-01 (CDH) and by the Sanfilippo Children’s Research Foundation (CDH).

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Authors and Affiliations

  1. Department of Medicine, University of Florida, Gainesville, FL, USA

    C D Heldermon

  2. Department of Internal Medicine, Washington University, St Louis, MO, USA

    E Y Qin & M S Sands

  3. Department of Otorhinolaryngology, Washington University, St Louis, MO, USA

    K K Ohlemiller

  4. Department of Biology, Washington University, St Louis, MO, USA

    E D Herzog

  5. Zacharon Pharmaceuticals, San Diego, CA, USA

    J R Brown & B E Crawford

  6. Department of Pathology, Saint Louis University, St Louis, MO, USA

    C Vogler

  7. Department of Biostatistics, University of Florida, Gainesville, FL, USA

    W Hou

  8. Department of Zoology, University of Wisconsin-Madison, Madison, WI, USA

    J L Orrock

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  1. C D Heldermon
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Correspondence to C D Heldermon or M S Sands.

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Jillian R Brown and Brett E Crawford are full-time employees and shareholders of Zacharon Pharmaceuticals. All other authors have no conflict of interest to report.

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Heldermon, C., Qin, E., Ohlemiller, K. et al. Disease correction by combined neonatal intracranial AAV and systemic lentiviral gene therapy in Sanfilippo Syndrome type B mice. Gene Ther 20, 913–921 (2013). https://doi.org/10.1038/gt.2013.14

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