Nathwani AC. Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program. 2019;2019:1–8.

Article  PubMed  PubMed Central  Google Scholar 

George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, et al. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N Engl J Med. 2021;385:1961–73.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, et al. Phase 1-2 trial of AAVS3 gene therapy in patients with hemophilia B. N Engl J Med. 2022;387:237–47.

Article  CAS  PubMed  Google Scholar 

Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, et al. GENEr8-1 Trial Group. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386:1013–25.

Article  CAS  PubMed  Google Scholar 

Naso MF, Tomkowicz B, Perry WL 3rd, Strohl WR. Adeno-associated virus (AAV) as a vector for gene therapy. BioDrugs. 2017;31:317–34.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jiang H, Couto LB, Patarroyo-White S, Liu T, Nagy D, Vargas JA, et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood. 2006;108:3321–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, et al. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342–7.

Article  CAS  PubMed  Google Scholar 

Pien GC, Basner-Tschakarjan E, Hui DJ, Mentlik AN, Finn JD, Hasbrouck NC, et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Invest. 2009;119:1688–95.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang L, Calcedo R, Bell P, Lin J, Grant RL, Siegel DL, et al. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum Gene Ther. 2011;22:1389–401.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Weber T. Anti-AAV antibodies in AAV gene therapy: current challenges and possible solutions. Front Immunol. 2021;12:658399.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Konkle BA, Walsh CE, Escobar MA, Josephson NC, Young G, von Drygalski A, et al. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood. 2021;137:763–74.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Klamroth R, Hayes G, Andreeva T, Gregg K, Suzuki T, Mitha IH, et al. Global seroprevalence of pre-existing immunity against AAV5 and other AAV serotypes in people with hemophilia A. Hum Gene Ther. 2022;33:432–41.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gorovits B, Fiscella M, Havert M, Koren E, Long B, Milton M, et al. Recommendations for the Development of Cell-Based Anti-Viral Vector Neutralizing Antibody Assays. AAPS J. 2020;22:24.

Article  PubMed  Google Scholar 

Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF, 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. 2010;21:704–12.

Article  CAS  PubMed  Google Scholar 

Schulz M, Levy DI, Petropoulos CJ, Bashirians G, Winburn I, Mahn M, et al. Binding and neutralizing anti-AAV antibodies: detection and implications for rAAV-mediated gene therapy. Mol Ther. 2023;31:616–30.

Article  CAS  PubMed  Google Scholar 

Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009;199:381–90.

Article  PubMed  Google Scholar 

Halbert CL, Miller AD, McNamara S, Emerson J, Gibson RL, Ramsey B, et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum Gene Ther. 2006;17:440–7.

Article  CAS  PubMed  Google Scholar 

Liu Q, Huang W, Zhang H, Wang Y, Zhao J, Song A, et al. Neutralizing antibodies against AAV2, AAV5 and AAV8 in healthy and HIV-1-infected subjects in China: implications for gene therapy using AAV vectors. Gene Ther. 2014;21:732–8.

Article  CAS  PubMed  Google Scholar 

Khatri A, Shelke R, Guan S, Somanathan S. Higher seroprevalence of anti-adeno-associated viral vector neutralizing antibodies among racial minorities in the United States. Hum Gene Ther. 2022;33:442–50.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Pogoda JM, et al. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure. Gene Ther. 2016;23:313–9.

Article  CAS  PubMed  Google Scholar 

Pipe SW, Leebeek FWG, Recht M, Key NS, Castaman G, Miesbach W, et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N Engl J Med. 2023;388:706–18.

Article  CAS  PubMed  Google Scholar 

Mahlangu J, Kaczmarek R, von Drygalski A, Shapiro S, Chou SC, Ozelo MC, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. 2023;388:694–705.

Article  CAS  PubMed  Google Scholar 

ROCTAVIAN [package insert on the internet]. Novato (CA): BioMarin Pharmaceutical Inc.; 2023.

Long BR, Sandza K, Holcomb J, Crockett L, Hayes GM, Arens J, et al. The impact of pre-existing immunity on the non-clinical pharmacodynamics of AAV5-based gene therapy. Mol Ther Methods Clin Dev. 2019;13:440–52.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Von Drygalski A, Giermasz A, Castaman G, Key NS, Lattimore S, Leebeek FWG, et al. Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv. 2019;3:3241–7.

Article  Google Scholar 

Majowicz A, Nijmeijer B, Lampen MH, Spronck L, de Haan M, Petry H, et al. Therapeutic hFIX activity achieved after single AAV5-hFIX treatment in hemophilia B patients and NHPs with pre-existing anti-AAV5 NABs. Mol Ther Methods Clin Dev. 2019;14:27–36.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gorovits B, Azadeh M, Buchlis G, Harrison T, Havert M, Jawa V, et al. Evaluation of the humoral response to adeno-associated virus-based gene therapy modalities using total antibody assays. AAPS J. 2021;23:108.

Article  CAS  PubMed  Google Scholar 

George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377:2215–27.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang M, Crosby A, Hastie E, Samulski JJ, McPhee S, Joshua G, et al. Prediction of adeno-associated virus neutralizing antibody activity for clinical application. Gene Ther. 2015;22:984–92.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kruzik A, Fetahagic D, Hartlieb B, Dorn S, Koppensteiner H, Horling FM, et al. Prevalence of anti-adeno-associated virus immune responses in international cohorts of healthy donors. Mol Ther Methods Clin Dev. 2019;14:126–33.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Murphy SL, Li H, Mingozzi F, Sabatino DE, Hui DJ, Edmonson SA, et al. Diverse IgG subclass responses to adeno-associated virus infection and vector administration. J Med Virol. 2009;81:65–74.

Article  PubMed  PubMed Central  Google Scholar 

Gardner MR, Mendes DE, Muniz CP, Martinez-Navio JM, Fuchs SP, Gao G, et al. High concordance of ELISA and neutralization assays allows for the detection of antibodies to individual AAV serotypes. Mol Ther Methods Clin Dev. 2022;24:199–206.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Qiu Q, Xu Z, Tian J, Moitra R, Gunti S, Notkins AL, et al. Impact of natural IgM concentration on gene therapy with adenovirus type 5 vectors. J Virol. 2015;89:3412–6.

Article  CAS  PubMed  Google Scholar 

Perocheau DP, Cunningham S, Lee J, Antinao Diaz J, Waddington SN, Gilmour K, et al. Age-related seroprevalence of antibodies against AAV-LK03 in a UK population cohort. Hum Gene Ther. 2019;30:79–87.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Harrington EA, Sloan JL, Manoli I, Chandler RJ, Schneider M, McGuire PJ, et al. Neutralizing antibodies against adeno-associated viral capsids in patients with mut methylmalonic acidemia. Hum Gene Ther. 2016;27:345–53.

Article