Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

C. Li; N. Narkbunnam; R. J. Samulski; A. Asokan; G. Hu; L. J. Jacobson; M. J. Manco-Johnson; P. E. Monahan; Brenda Riske; Ray Kilcoyne; Sharon Funk; Linda Jacobson; J. David Ingram; Thomas C. Abshire; Amy D. Shapiro; Michele R. Hacker; Leonard A. Valentino; W. Keith Hoots; Deborah Brown; George R. Buchanan; Donna DiMichele; Michael Recht; Cindy Leissinger; Shirley Bleak; Alan Cohen; Prasad Mathew; Alison Matsunaga; Desiree Medeiros; Diane Nugent; Gregory A. Thomas; Alexis A. Thompson; Kevin McRedmond; J. Michael Soucie; Harlan Austin; Bruce L. Evatt

doi:10.1038/gt.2011.90

Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

C. Li, N. Narkbunnam, R. J. Samulski, A. Asokan, G. Hu, L. J. Jacobson, M. J. Manco-Johnson, P. E. Monahan, Brenda Riske, Ray Kilcoyne, Sharon Funk, Linda Jacobson, J. David Ingram, Thomas C. Abshire, Amy D. Shapiro, Michele R. Hacker, Leonard A. Valentino, W. Keith Hoots, Deborah Brown, George R. BuchananDonna DiMichele, Michael Recht, Cindy Leissinger, Shirley Bleak, Alan Cohen, Prasad Mathew, Alison Matsunaga, Desiree Medeiros, Diane Nugent, Gregory A. Thomas, Alexis A. Thompson, Kevin McRedmond, J. Michael Soucie, Harlan Austin, Bruce L. Evatt

Pediatrics

Research output: Contribution to journal › Article › peer-review

168 Scopus citations

Abstract

Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

Original language	English (US)
Pages (from-to)	288-294
Number of pages	7
Journal	Gene therapy
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/gt.2011.90
State	Published - Mar 1 2012

Keywords

AAV
children
hemophilia
neutralizing antibody
prevalence
serotype

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics

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10.1038/gt.2011.90

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Li, C., Narkbunnam, N., Samulski, R. J., Asokan, A., Hu, G., Jacobson, L. J., Manco-Johnson, M. J., Monahan, P. E., Riske, B., Kilcoyne, R., Funk, S., Jacobson, L., Ingram, J. D., Abshire, T. C., Shapiro, A. D., Hacker, M. R., Valentino, L. A., Hoots, W. K., Brown, D., ... Evatt, B. L. (2012). Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene therapy, 19(3), 288-294. https://doi.org/10.1038/gt.2011.90

Li, C, Narkbunnam, N, Samulski, RJ, Asokan, A, Hu, G, Jacobson, LJ, Manco-Johnson, MJ, Monahan, PE, Riske, B, Kilcoyne, R, Funk, S, Jacobson, L, Ingram, JD, Abshire, TC, Shapiro, AD, Hacker, MR, Valentino, LA, Hoots, WK, Brown, D, Buchanan, GR, DiMichele, D, Recht, M, Leissinger, C, Bleak, S, Cohen, A, Mathew, P, Matsunaga, A, Medeiros, D, Nugent, D, Thomas, GA, Thompson, AA, McRedmond, K, Soucie, JM, Austin, H & Evatt, BL 2012, 'Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia', Gene therapy, vol. 19, no. 3, pp. 288-294. https://doi.org/10.1038/gt.2011.90

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title = "Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia",

abstract = "Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.",

keywords = "AAV, children, hemophilia, neutralizing antibody, prevalence, serotype",

author = "C. Li and N. Narkbunnam and Samulski, {R. J.} and A. Asokan and G. Hu and Jacobson, {L. J.} and Manco-Johnson, {M. J.} and Monahan, {P. E.} and Brenda Riske and Ray Kilcoyne and Sharon Funk and Linda Jacobson and Ingram, {J. David} and Abshire, {Thomas C.} and Shapiro, {Amy D.} and Hacker, {Michele R.} and Valentino, {Leonard A.} and Hoots, {W. Keith} and Deborah Brown and Buchanan, {George R.} and Donna DiMichele and Michael Recht and Cindy Leissinger and Shirley Bleak and Alan Cohen and Prasad Mathew and Alison Matsunaga and Desiree Medeiros and Diane Nugent and Thomas, {Gregory A.} and Thompson, {Alexis A.} and Kevin McRedmond and Soucie, {J. Michael} and Harlan Austin and Evatt, {Bruce L.}",

note = "Funding Information: We thank Matt Hirsch for his critical reading and comments. This work was in part supported from NIH research grants 1R01AI080726 and 5R01DK084033 (to CL and RJS), 5U54AR056953 and 5R01AI072176 (to RJS). This report documents a satellite study of the Joint Outcome Study; the parent study JOS was supported by grants from the Centers for Disease Control and Prevention (U27/CCU812106) and the National Institutes of Health (R00069) and additionally received support from Bayer HealthCare and the Hemophilia and Thrombosis Research Society.",

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doi = "10.1038/gt.2011.90",

language = "English (US)",

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T1 - Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

AU - Li, C.

AU - Narkbunnam, N.

AU - Samulski, R. J.

AU - Asokan, A.

AU - Hu, G.

AU - Jacobson, L. J.

AU - Manco-Johnson, M. J.

AU - Monahan, P. E.

AU - Riske, Brenda

AU - Kilcoyne, Ray

AU - Funk, Sharon

AU - Jacobson, Linda

AU - Ingram, J. David

AU - Abshire, Thomas C.

AU - Shapiro, Amy D.

AU - Hacker, Michele R.

AU - Valentino, Leonard A.

AU - Hoots, W. Keith

AU - Brown, Deborah

AU - Buchanan, George R.

AU - DiMichele, Donna

AU - Recht, Michael

AU - Leissinger, Cindy

AU - Bleak, Shirley

AU - Cohen, Alan

AU - Mathew, Prasad

AU - Matsunaga, Alison

AU - Medeiros, Desiree

AU - Nugent, Diane

AU - Thomas, Gregory A.

AU - Thompson, Alexis A.

AU - McRedmond, Kevin

AU - Soucie, J. Michael

AU - Austin, Harlan

AU - Evatt, Bruce L.

N1 - Funding Information: We thank Matt Hirsch for his critical reading and comments. This work was in part supported from NIH research grants 1R01AI080726 and 5R01DK084033 (to CL and RJS), 5U54AR056953 and 5R01AI072176 (to RJS). This report documents a satellite study of the Joint Outcome Study; the parent study JOS was supported by grants from the Centers for Disease Control and Prevention (U27/CCU812106) and the National Institutes of Health (R00069) and additionally received support from Bayer HealthCare and the Hemophilia and Thrombosis Research Society.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

AB - Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.

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KW - children

KW - hemophilia

KW - neutralizing antibody

KW - prevalence

KW - serotype

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Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia

Abstract

Keywords

ASJC Scopus subject areas

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