Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure

被引：88

作者：

Greenberg, B. ^{[1
]}

Butler, J. ^{[2
]}

Felker, G. M. ^{[3
]}

Ponikowski, P. ^{[4
]}

Voors, A. A. ^{[5
]}

Pogoda, J. M. ^{[6
]}

Provost, R. ^{[6
]}

Guerrero, J. ^{[6
]}

Hajjar, R. J. ^{[7
]}

Zsebo, K. M. ^{[8
]}

机构：

[1] Univ Calif San Diego, Sulpizio Cardiovasc Ctr, 9444 Med Ctr Dr,7411, La Jolla, CA 92037 USA

[2] SUNY Stony Brook, Stony Brook, NY 11794 USA

[3] Duke Univ, Sch Med, Durham, NC USA

[4] Wroclaw Med Univ & Mil Hosp, Wroclaw, Poland

[5] Univ Groningen, Groningen, Netherlands

[6] Celladon Corp, San Diego, CA USA

[7] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA

[8] Biovest Consulting LLC, Santa Barbara, CA USA

来源：

GENE THERAPY | 2016年 / 23卷 / 03期

关键词：

CALCIUM UP-REGULATION; ADENOASSOCIATED VIRUS AAV; THERAPY; EXPRESSION; PLASMAPHERESIS; HEMOPHILIA; RESPONSES; DELIVERY; VECTOR; IMPACT;

D O I：

10.1038/gt.2015.109

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P = 0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.

引用

页码：313 / 319

页数：7

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