Safety and efficacy of gene transfer for Leber's congenital amaurosis

Albert M. Maguire; Francesca Simonelli; Eric A. Pierce; Edward N. Pugh; Federico Mingozzi; Jeannette Bennicelli; Sandro Banfi; Kathleen A. Marshall; Francesco Testa; Enrico M. Surace; Settimio Rossi; Arkady Lyubarsky; Valder R. Arruda; Barbara Konkle; Edwin Stone; Junwei Sun; Jonathan Jacobs; Lou Dell'Osso; Richard Hertle; Jian Xing Ma; T. Michael Redmond; Xiaosong Zhu; Bernd Hauck; Olga Zelenaia; Kenneth S. Shindler; Maureen G. Maguire; J. Fraser Wright; Nicholas J. Volpe; Jennifer Wellman McDonnell; Alberto Auricchio; Katherine A. High; Jean Bennett

doi:10.1056/NEJMoa0802315

Safety and efficacy of gene transfer for Leber's congenital amaurosis

Albert M. Maguire, Francesca Simonelli, Eric A. Pierce, Edward N. Pugh, Federico Mingozzi, Jeannette Bennicelli, Sandro Banfi, Kathleen A. Marshall, Francesco Testa, Enrico M. Surace, Settimio Rossi, Arkady Lyubarsky, Valder R. Arruda, Barbara Konkle, Edwin Stone, Junwei Sun, Jonathan Jacobs, Lou Dell'Osso, Richard Hertle, Jian Xing MaT. Michael Redmond, Xiaosong Zhu, Bernd Hauck, Olga Zelenaia, Kenneth S. Shindler, Maureen G. Maguire, J. Fraser Wright, Nicholas J. Volpe, Jennifer Wellman McDonnell, Alberto Auricchio, Katherine A. High, Jean Bennett^*

^*Corresponding author for this work

Ophthalmology

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

1877 Scopus citations

Abstract

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

Original language	English (US)
Pages (from-to)	2240-2248
Number of pages	9
Journal	New England Journal of Medicine
Volume	358
Issue number	21
DOIs	https://doi.org/10.1056/NEJMoa0802315
State	Published - May 22 2008

Funding

Supported by the Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, the Foundation Fighting Blindness sponsored by the Pediatric Center for Retinal Degenerations, Research to Prevent Blindness, a grant (EY-10820) from the National Institutes of Health, the Macula Vision Foundation, the Paul and Evanina Mackall Foundation Trust, the Scheie Eye Institute, the F.M. Kirby Foundation, grants (TIGEM-P21, to Drs. Auricchio, Surace, and Banfi, and GGP07180, to Dr. Simonelli) from the Italian Telethon Foundation, a grant (UL1-RR-024134) from the National Center for Research Resources, the Rosanne H. Silbermann Foundation, the Associazione Italiana Amaurosi Congenita di Leber, and the Howard Hughes Medical Institute (to Drs. Stone and High).

ASJC Scopus subject areas

General Medicine

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Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., Rossi, S., Lyubarsky, A., Arruda, V. R., Konkle, B., Stone, E., Sun, J., Jacobs, J., Dell'Osso, L., Hertle, R., ... Bennett, J. (2008). Safety and efficacy of gene transfer for Leber's congenital amaurosis. New England Journal of Medicine, 358(21), 2240-2248. https://doi.org/10.1056/NEJMoa0802315

@article{935a60a07b4f4259a2b3e04a0f7c8991,

title = "Safety and efficacy of gene transfer for Leber's congenital amaurosis",

abstract = "Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.",

author = "Maguire, {Albert M.} and Francesca Simonelli and Pierce, {Eric A.} and Pugh, {Edward N.} and Federico Mingozzi and Jeannette Bennicelli and Sandro Banfi and Marshall, {Kathleen A.} and Francesco Testa and Surace, {Enrico M.} and Settimio Rossi and Arkady Lyubarsky and Arruda, {Valder R.} and Barbara Konkle and Edwin Stone and Junwei Sun and Jonathan Jacobs and Lou Dell'Osso and Richard Hertle and Ma, {Jian Xing} and Redmond, {T. Michael} and Xiaosong Zhu and Bernd Hauck and Olga Zelenaia and Shindler, {Kenneth S.} and Maguire, {Maureen G.} and Wright, {J. Fraser} and Volpe, {Nicholas J.} and McDonnell, {Jennifer Wellman} and Alberto Auricchio and High, {Katherine A.} and Jean Bennett",

note = "Funding Information: Supported by the Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, the Foundation Fighting Blindness sponsored by the Pediatric Center for Retinal Degenerations, Research to Prevent Blindness, a grant (EY-10820) from the National Institutes of Health, the Macula Vision Foundation, the Paul and Evanina Mackall Foundation Trust, the Scheie Eye Institute, the F.M. Kirby Foundation, grants (TIGEM-P21, to Drs. Auricchio, Surace, and Banfi, and GGP07180, to Dr. Simonelli) from the Italian Telethon Foundation, a grant (UL1-RR-024134) from the National Center for Research Resources, the Rosanne H. Silbermann Foundation, the Associazione Italiana Amaurosi Congenita di Leber, and the Howard Hughes Medical Institute (to Drs. Stone and High). ",

year = "2008",

month = may,

day = "22",

doi = "10.1056/NEJMoa0802315",

language = "English (US)",

volume = "358",

pages = "2240--2248",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "21",

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Maguire, AM, Simonelli, F, Pierce, EA, Pugh, EN, Mingozzi, F, Bennicelli, J, Banfi, S, Marshall, KA, Testa, F, Surace, EM, Rossi, S, Lyubarsky, A, Arruda, VR, Konkle, B, Stone, E, Sun, J, Jacobs, J, Dell'Osso, L, Hertle, R, Ma, JX, Redmond, TM, Zhu, X, Hauck, B, Zelenaia, O, Shindler, KS, Maguire, MG, Wright, JF, Volpe, NJ, McDonnell, JW, Auricchio, A, High, KA & Bennett, J 2008, 'Safety and efficacy of gene transfer for Leber's congenital amaurosis', New England Journal of Medicine, vol. 358, no. 21, pp. 2240-2248. https://doi.org/10.1056/NEJMoa0802315

TY - JOUR

T1 - Safety and efficacy of gene transfer for Leber's congenital amaurosis

AU - Maguire, Albert M.

AU - Simonelli, Francesca

AU - Pierce, Eric A.

AU - Pugh, Edward N.

AU - Mingozzi, Federico

AU - Bennicelli, Jeannette

AU - Banfi, Sandro

AU - Marshall, Kathleen A.

AU - Testa, Francesco

AU - Surace, Enrico M.

AU - Rossi, Settimio

AU - Lyubarsky, Arkady

AU - Arruda, Valder R.

AU - Konkle, Barbara

AU - Stone, Edwin

AU - Sun, Junwei

AU - Jacobs, Jonathan

AU - Dell'Osso, Lou

AU - Hertle, Richard

AU - Ma, Jian Xing

AU - Redmond, T. Michael

AU - Zhu, Xiaosong

AU - Hauck, Bernd

AU - Zelenaia, Olga

AU - Shindler, Kenneth S.

AU - Maguire, Maureen G.

AU - Wright, J. Fraser

AU - Volpe, Nicholas J.

AU - McDonnell, Jennifer Wellman

AU - Auricchio, Alberto

AU - High, Katherine A.

AU - Bennett, Jean

N1 - Funding Information: Supported by the Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, the Foundation Fighting Blindness sponsored by the Pediatric Center for Retinal Degenerations, Research to Prevent Blindness, a grant (EY-10820) from the National Institutes of Health, the Macula Vision Foundation, the Paul and Evanina Mackall Foundation Trust, the Scheie Eye Institute, the F.M. Kirby Foundation, grants (TIGEM-P21, to Drs. Auricchio, Surace, and Banfi, and GGP07180, to Dr. Simonelli) from the Italian Telethon Foundation, a grant (UL1-RR-024134) from the National Center for Research Resources, the Rosanne H. Silbermann Foundation, the Associazione Italiana Amaurosi Congenita di Leber, and the Howard Hughes Medical Institute (to Drs. Stone and High).

PY - 2008/5/22

Y1 - 2008/5/22

N2 - Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

AB - Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 21

ER -

Safety and efficacy of gene transfer for Leber's congenital amaurosis

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