Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models

Human Gene Therapy

Volumn 28, Issue 4, 2017, Pages 314-322

  Chandler, Randy J ^a   Sands, Mark S ^b   Venditti, Charles P ^a  

^a NATIONAL HUMAN GENOME RESEARCH INSTITUTE   (United States)

^b WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AAV; cancer; gene therapy; genotoxicity; HCC; insertional mutagenesis

Indexed keywords

ADENO ASSOCIATED VIRUS VECTOR;

ARTICLE; GENOTOXICITY; HUMAN; LIVER CELL CARCINOMA; MUTAGENESIS; NONHUMAN; VIRAL GENE DELIVERY SYSTEM; VIRAL GENE THERAPY; VIRUS RECOMBINANT; ADVERSE EFFECTS; ANIMAL; DEPENDOPARVOVIRUS; GENE THERAPY; GENE TRANSFER; GENETICS; MOUSE; PROCEDURES;

ANIMALS; DEPENDOVIRUS; GENE TRANSFER TECHNIQUES; GENETIC THERAPY; HUMANS; MICE;

EID: 85018506247     PISSN: 10430342     EISSN: 15577422     Source Type: Journal    
DOI: 10.1089/hum.2017.009     Document Type: Article

References (57)

1. Naldini L. Gene therapy returns to centre stage. Nature 2015;526:351-360.
2. Bender E. Gene therapy: industrial strength. Nature 2016;537:S57-59.
3. Schimmer J, Breazzano S. Investor outlook: gene therapy picking up steam; at a crossroads. Hum Gene Ther Clin Dev 2016;27:87-92.
4. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348:255-256.
5. Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80:148-158.
6. Li Z, Dullmann J, Schiedlmeier B, et al. Murine leukemia induced by retroviral gene marking. Science 2002;296:497.
7. Bruder JT, Kovesdi I. Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression. J Virol 1997;71: 398-404.
8. Schnepp BC, Clark KR, Klemanski DL, et al. Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J Virol 2003;77:3495-3504.
9. Schnepp BC, Jensen RL, Chen CL, et al. Characterization of adeno-associated virus genomes isolated from human tissues. J Virol 2005;79: 14793-14803.
10. Asokan A, Schaffer DV, Samulski RJ. The AAV vector toolkit: poised at the clinical crossroads. Mol Ther 2012;20:699-708.
11. Mueller C, Flotte TR. Clinical gene therapy using recombinant adeno-associated virus vectors. Gene Ther 2008;15:858-863.
12. Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 2011;12:341-355.
13. Daya S, Berns KI. Gene therapy using adenoassociated virus vectors. Clin Microbiol Rev 2008;21:583-593.
14. LeFebvre RB, Berns KI. Unique events in parvovirus replication. Microbiol Sci 1984;1:163-167.
15. Bohenzky RA, LeFebvre RB, Berns KI. Sequence and symmetry requirements within the internal palindromic sequences of the adeno-associated virus terminal repeat. Virology 1988;166:316-327.
16. Samulski RJ, Chang LS, Shenk T. Helper-free stocks of recombinant adeno-associated viruses: normal integration does not require viral gene expression. J Virol 1989;63:3822-3828.
17. Samulski RJ, Zhu X, Xiao X, et al. Targeted integration of adeno-associated virus (AAV) into human chromosome 19. Embo J 1991;10:3941-3950.
18. Kotin RM, Siniscalco M, Samulski RJ, et al. Sitespecific integration by adeno-associated virus. Proc Natl Acad Sci U S A 1990;87:2211-2215.
19. Kotin RM, Menninger JC, Ward DC, et al. Mapping and direct visualization of a region-specific viral DNA integration site on chromosome 19q13-qter. Genomics 1991;10:831-834.
20. Grimm D, Kern A, Rittner K, et al. Novel tools for production and purification of recombinant adenoassociated virus vectors. Hum Gene Ther 1998;9:2745-2760.
21. Nakai H, Montini E, Fuess S, et al. AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat Genet 2003;34:297-302.
22. Duan D, Sharma P, Yang J, et al. Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J Virol 1998;72:8568-8577.
23. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006;12:342-347.
24. Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol GenetMetab 2003;80:148-158.
25. Jooss K, Yang Y, Fisher KJ, et al. Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers. J Virol 1998;72:4212-4223.
26. Somanathan S, Breous E, Bell P, et al. AAV vectors avoid inflammatory signals necessary to render transduced hepatocyte targets for destructive T cells. Mol Ther 2010;18:977-982.
27. Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014;371: 1994-2004.
28. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302:415-419.
29. Braun CJ, Boztug K, Paruzynski A, et al. Gene therapy for Wiskott-Aldrich syndrome - long-term efficacy and genotoxicity. Sci Transl Med 2014;6:227ra233.
30. Part 16: Lysosomal Disorders. In: Valle D, Beaudet AL, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill Global Education Holdings, LLC, 2017.
31. Sands MS, Davidson BL. Gene therapy for lysosomal storage diseases. Mol Ther 2006;13:839-849.
32. Neufeld EF, Fratantoni JC. Inborn errors of mucopolysaccharide metabolism. Science 1970;169: 141-146.
33. Sly WS, Quinton BA, McAlister WH, et al. Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J Pediatr 1973;82:249-257.
34. Birkenmeier EH, Davisson MT, Beamer WG, et al. Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J Clin Invest 1989;83:1258-1266.
35. Sands MS, Birkenmeier EH. A single-base-pair deletion in the beta-glucuronidase gene accounts for the phenotype of murine mucopolysaccharidosis type VII. Proc Natl Acad Sci U S A 1993;90:6567-6571.
36. Daly TM, Vogler C, Levy B, et al. Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc Natl Acad Sci U S A 1999;96:2296-2300.
37. Daly TM, Okuyama T, Vogler C, et al. Neonatal intramuscular injection with recombinant adenoassociated virus results in prolonged betaglucuronidase expression in situ and correction of liver pathology in mucopolysaccharidosis type VII mice. Hum Gene Ther 1999;10:85-94.
38. Daly TM, Ohlemiller KK, Roberts MS, et al. Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer. Gene Ther 2001;8:1291-1298.
39. Donsante A, Vogler C, Muzyczka N, et al. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther 2001;8:1343-1346.
40. Donsante A, Miller DG, Li Y, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 2007;317:477.
41. Wang PR, Xu M, Toffanin S, et al. Induction of hepatocellular carcinoma by in vivo gene targeting. Proc Natl Acad Sci U S A 2012;109:11264-11269.
42. Embury JE, Frost S, Charron CE, et al. Hepatitis virus protein X-phenylalanine hydroxylase fusion proteins identified in PKU mice treated with AAVWPRE vectors. Gene Ther Mol Biol 2008;12:69-76.
43. Bell P, Moscioni AD, McCarter RJ, et al. Analysis of tumors arising in male B6C3F1 mice with and without AAV vector delivery to liver. Mol Ther 2006;14:34-44.
44. Zhong L, Malani N, Li M, et al. Recombinant adeno-associated virus integration sites in murine liver after ornithine transcarbamylase gene correction. Hum Gene Ther 2013;24:520-525.
45. Bell P, Wang L, Lebherz C, et al. No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol Ther 2005;12:299-306.
46. Li H, Malani N, Hamilton SR, et al. Assessing the potential for AAV vector genotoxicity in a murine model. Blood 2011;117:3311-3319.
47. Kao CY, Yang SJ, Tao MH, et al. Incorporation of the factor IX Padua mutation into FIX-Triple improves clotting activity in vitro and in vivo. Thromb Haemost 2013;110:244-256.
48. Rosas LE, Grieves JL, Zaraspe K, et al. Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol Ther 2012;20:2098-2110.
49. Walia JS, Altaleb N, Bello A, et al. Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates. Mol Ther 2015;23:414-422.
50. Chandler RJ, LaFave MC, Varshney GK, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest 2015;125:870-880.
51. Ranzani M, Cesana D, Bartholomae CC, et al. Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer. Nat Methods 2013;10:155-161.
52. Dupuy AJ, Rogers LM, Kim J, et al. A modified sleeping beauty transposon system that can be used to model a wide variety of human cancers in mice. Cancer Res 2009;69:8150-8156.
53. Nault JC, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet 2015;47:1187-1193.
54. Paneda A, Lopez-Franco E, Kaeppel C, et al. Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute intermittent porphyria. Hum Gene Ther 2013;24:1007-1017.
55. Cunningham SC, Siew SM, Hallwirth CV, et al. Modeling correction of severe urea cycle defects in the growing murine liver using a hybrid recombinant adeno-associated virus/piggyBac transposase gene delivery system. Hepatology 2015;62:417-428.
56. Gil-Farina I, Fronza R, Kaeppel C, et al. Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol Ther 2016;24:1100-1105.
57. Reiss J, Hahnewald R. Molybdenum cofactor deficiency: mutations in GPHN, MOCS1, and MOCS2. Hum Mutat 2011;32:10-18.