Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration

Nature Communications

Volumn 9, Issue 1, 2018, Pages

  Meliani, Amine ^a,b   Boisgerault, Florence ^b   Hardet, Romain ^a   Marmier, Solenne ^a   Collaud, Fanny ^b   Ronzitti, Giuseppe ^b   Leborgne, Christian ^b   Costa Verdera, Helena ^a,b   Simon Sola, Marcelo ^a,b   Charles, Severine ^b   Vignaud, Alban ^b   van Wittenberghe, Laetitia ^b   Manni, Giorgia ^c   Christophe, Olivier ^d   Fallarino, Francesca ^c   Roy, Christopher ^e   Michaud, Alicia ^e   Ilyinskii, Petr ^e   Kishimoto, Takashi Kei ^e   Mingozzi, Federico ^a,b  

^a SORBONNE UNIVERSITÉ   (France)

^b UNIVERSITÉ D EVRY VAL D ESSONNE   (France)

^c UNIVERSITY OF PERUGIA   (Italy)

^d Dept Environ Med Natl Inst Publ HIth   (Norway)

^e Selecta Biosciences   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTICS; CELL COMPONENT; DISEASE; GENE; GENE EXPRESSION; GENE TRANSFER; INFILTRATION; MEMORY; NANOPARTICLE; PRIMATE; RECOMBINATION; VACCINE; VECTOR; VIRUS;

ADENO-ASSOCIATED VIRUS; MIRIDAE; MUS; PRIMATES;

IMMUNOSUPPRESSIVE AGENT; NANOPARTICLE; RAPAMYCIN;

ANIMAL; C57BL MOUSE; CELLULAR IMMUNITY; DEPENDOPARVOVIRUS; DRUG EFFECT; GENE THERAPY; GENE VECTOR; HUMORAL IMMUNITY; IMMUNOLOGY; MACACA FASCICULARIS; MALE; PRECLINICAL STUDY; T LYMPHOCYTE;

ANIMALS; DEPENDOVIRUS; DRUG EVALUATION, PRECLINICAL; GENETIC THERAPY; GENETIC VECTORS; IMMUNITY, CELLULAR; IMMUNITY, HUMORAL; IMMUNOSUPPRESSIVE AGENTS; MACACA FASCICULARIS; MALE; MICE, INBRED C57BL; NANOPARTICLES; SIROLIMUS; T-LYMPHOCYTES;

EID: 85054427947     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/s41467-018-06621-3     Document Type: Article

References (60)

1. Mingozzi, F. & High, K. A. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat. Rev. Genet. 12, 341–355 (2011)
2. George, L. A. et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N. Engl. J. Med. 377, 2215–2227 (2017)
3. Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat. Med. 12, 342–347 (2006)
4. Miesbach, W. et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood 131, 1022–1031 (2018)
5. Nathwani, A. C. et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371, 1994–2004 (2014)
6. Nathwani, A. C. et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N. Engl. J. Med. 365, 2357–2365 (2011)
7. Rangarajan, S. et al. AAV5-factor VIII gene transfer in severe hemophilia A. N. Engl. J. Med. 377, 2519–2530 (2017)
8. Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017)
9. Russell, S. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 390, 849–860 (2017)
10. Fagiuoli, S., Daina, E., D’Antiga, L., Colledan, M. & Remuzzi, G. Monogenic diseases that can be cured by liver transplantation. J. Hepatol. 59, 595–612 (2013)
11. Soriano, H. E. & Grompe, M. Gene therapy and pediatric liver disease. J. Pediatr. Gastroenterol. Nutr. 35(Suppl 1), S51–S54 (2002)
12. Bortolussi, G. et al. Life-long correction of hyperbilirubinemia with a neonatal liver-specific AAV-mediated gene transfer in a lethal mouse model of Crigler-Najjar Syndrome. Hum. Gene Ther. 25, 844–855 (2014)
13. Ronzitti, G. et al. A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. Mol. Ther. Methods Clin. Dev. 3, 16049 (2016)
14. Wang, L., Wang, H., Bell, P., McMenamin, D. & Wilson, J. M. Hepatic gene transfer in neonatal mice by adeno-associated virus serotype 8 vector. Hum. Gene Ther. 23, 533–539 (2012)
15. Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018)
16. Mingozzi, F. & High, K. A. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape. Annu Rev. Virol. 4, 511–534 (2017)
17. Mingozzi, F. et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat. Med. 13, 419–422 (2007)
18. Kishimoto, T. K. et al. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. Nat. Nanotechnol. 11, 890–899 (2016)
19. Maldonado, R. A. et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc. Natl Acad. Sci. USA 112, E156–E165 (2015)
20. Lim, H. H. et al. A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease. Mol. Genet. Metab. Rep. 13, 18–22 (2017)
21. Mazor, R. et al. Tolerogenic nanoparticles restore the antitumor activity of recombinant immunotoxins by mitigating immunogenicity. Proc. Natl Acad. Sci. USA 115, E733–E742 (2018)
22. Sands, E., Kivitz, A. J., DeHaan, W., Johnston, L., & Kishimoto, T. K. Initial phase 2 clinical data of SEL-212 in symptomatic gout patients: monthly dosing of a pegylated uricase (pegsiticase) with SVP-rapamycin enables sustained reduction of serum uric acid levels by mitigating formation of anti-drug antibodies. Arthritis Rheumatol. 69, abstract 2091 (2017)
23. Zhang, A. H., Rossi, R. J., Yoon, J., Wang, H. & Scott, D. W. Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation. Cell Immunol. 301, 74–81 (2016)
24. Meliani, A. et al. Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system. Hum. Gene Ther. Methods 26, 45–53 (2015)
25. Mingozzi, F. et al. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci. Transl. Med. 5, 194ra192 (2013)
26. Sun, L. et al. Assessment of a passive immunity mouse model to quantitatively analyze the impact of neutralizing antibodies on adeno-associated virus-mediated gene transfer. J. Immunol. Methods 387, 114–120 (2013)
27. Hui, D. J. et al. Modulation of CD8+T cell responses to AAV vectors with IgG-derived MHC class II epitopes. Mol. Ther. 21, 1727–1737 (2013)
28. Corti, M. et al. B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study. Mol. Ther. Methods Clin. Dev. 1, 14033 (2014)
29. Mingozzi, F. et al. Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B. Mol. Ther. 20, 1410–1416 (2012)
30. Hui, D. J. et al. AAV capsid CD8+T-cell epitopes are highly conserved across AAV serotypes. Mol. Ther. Methods Clin. Dev. 2, 15029 (2015)
31. Veron, P. et al. Humoral and cellular capsid-specific immune responses to adeno-associated virus type 1 in randomized healthy donors. J. Immunol. 188, 6418–6424 (2012)
32. Mays, L. E. et al. AAV8 induces tolerance in murine muscle as a result of poor APC transduction, T cell exhaustion, and minimal MHCI upregulation on target cells. Mol. Ther. 22, 28–41 (2014)
33. Tseng, Y. S. & Agbandje-McKenna, M. Mapping the AAV capsid host antibody response toward the development of second generation gene delivery vectors. Front. Immunol. 5, 9 (2014)
34. Jiang, H. et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood 108, 3321–3328 (2006)
35. Le Guiner, C. et al. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nat. Commun. 8, 16105 (2017)
36. Elverman, M. et al. Long-term effects of systemic gene therapy in a canine model of myotubular myopathy. Muscle Nerve 56, 943–953 (2017)
37. Greig, J. A. et al. Intramuscular administration of AAV overcomes pre-existing neutralizing antibodies in rhesus macaques. Vaccine 34, 6323–6329 (2016)
38. Amado, D. et al. Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci. Transl. Med. 2, 21ra16 (2010)
39. Bennett, J. et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci. Transl. Med. 4, 120ra115 (2012)
40. Manno, C. S. et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101, 2963–2972 (2003)
41. Herzog, R. W. Hemophilia gene therapy: caught between a cure and an immune response. Mol. Ther. 23, 1411–1412 (2015)
42. Pipe, S. et al. 101HEMB01 is a phase 1/2 open-label, single ascending dose-finding trial of DTX101 (AAVrh10FIX) in patients with moderate/severe hemophilia B that demonstrated meaningful but transient expression of human factor IX (hFIX). Blood 130, 604 (2017)
43. Li, H. et al. Pre-existing AAV capsid-specific CD8+T cells are unable to eliminate AAV-transduced hepatocytes. Mol. Ther. 15, 792–800 (2007)
44. Mingozzi, F. et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 110, 2334–2341 (2007)
45. Unzu, C. et al. Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. J. Transl. Med. 10, 122 (2012)
46. Cao, O. et al. Impact of the underlying mutation and the route of vector administration on immune responses to factor IX in gene therapy for hemophilia B. Mol. Ther. 17, 1733–1742 (2009)
47. Chicoine, L. G. et al. Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol. Ther. 22, 338–347 (2014)
48. Monteilhet, V. et al. A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Mol. Ther. 19, 2084–2091 (2011)
49. Majowicz, A. et al. Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5(ch) and AAV1. Mol. Ther. 25, 1831–1842 (2017)
50. Boutin, S. et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum. Gene Ther. 21, 704–712 (2010)
51. Battaglia, M. et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+regulatory T cells of both healthy subjects and type 1 diabetic patients. J. Immunol. 177, 8338–8347 (2006)
52. Mingozzi, F. et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J. Clin. Invest. 111, 1347–1356 (2003)
53. Mauri, C. & Menon, M. Human regulatory B cells in health and disease: therapeutic potential. J. Clin. Invest. 127, 772–779 (2017)
54. Kazi, Z. B. et al. Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses. JCI Insight 1, e86821 (2016)
55. Ayuso, E. et al. High AAV vector purity results in serotype- and tissue-independent enhancement of transduction efficiency. Gene Ther. 17, 503–510 (2010)
56. Matsushita, T. et al. Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther. 5, 938–945 (1998)
57. Charan, J. & Kantharia, N. D. How to calculate sample size in animal studies? J. Pharmacol. Pharmacother. 4, 303–306 (2013)
58. Puzzo, F. et al. Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid alpha-glucosidase. Sci. Translat. Med. 9, eaam6375 (2017)
59. Meliani, A. et al. Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors. Blood Adv. 1, 2019–2031 (2017)
60. Ito, T. et al. A convenient enzyme-linked immunosorbent assay for rapid screening of anti-adeno-associated virus neutralizing antibodies. Ann. Clin. Biochem. 46, 508–510 (2009)