TY - JOUR
T1 - Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis
T2 - a phase 1 dose-escalation trial
AU - Maguire, Albert M.
AU - High, Katherine A.
AU - Auricchio, Alberto
AU - Wright, J. Fraser
AU - Pierce, Eric A.
AU - Testa, Francesco
AU - Mingozzi, Federico
AU - Bennicelli, Jeannette L.
AU - Ying, Gui shuang
AU - Rossi, Settimio
AU - Fulton, Ann
AU - Marshall, Kathleen A.
AU - Banfi, Sandro
AU - Chung, Daniel C.
AU - Morgan, Jessica IW
AU - Hauck, Bernd
AU - Zelenaia, Olga
AU - Zhu, Xiaosong
AU - Raffini, Leslie
AU - Coppieters, Frauke
AU - De Baere, Elfride
AU - Shindler, Kenneth S.
AU - Volpe, Nicholas J.
AU - Surace, Enrico M.
AU - Acerra, Carmela
AU - Lyubarsky, Arkady
AU - Redmond, T. Michael
AU - Stone, Edwin
AU - Sun, Junwei
AU - McDonnell, Jennifer Wellman
AU - Leroy, Bart P.
AU - Simonelli, Francesca
AU - Bennett, Jean
N1 - Funding Information:
The CHOP, a non-profit entity with a mission to develop novel therapeutics for inherited disorders, was the main source of funding for this study. The Visual Function Questionnaire-25 was developed by RAND (Santa Monica, CA, USA) and funded by National Eye Institute-National Institutes of Health (Bethesda, MD, USA). The Foundation Fighting Blindness (Owings Mills, MD, USA) sponsored CHOP-PENN Pediatric Center for Retinal Degenerations, Research to Prevent Blindness (New York, NY, USA), Macula Vision Research Foundation (West Conshohocken, PA, USA), Paul and Evanina Mackall Foundation Trust at the Scheie Eye Institute, and F M Kirby Foundation (Philadelphia, PA, USA). This work was also supported with grants from Telethon (Naples, Italy ; numbers TIGEM-P21 to AA, EMS, and SB at TIGEM, and GGP07180 to FS); Regione Campania Convenzione ( 66 del DPR 382/80 to FS); and European Union ( 018933 Clinigene and 223445 AAVEYE to AA). We thank the Foundation for Retinal Research and Associazione Italiana Amaurosi Congenita di Leber for their support. FC is a doctoral student supported by the Fund for Scientific Research (FWO) Flanders grant ( 1.1.387.07.N.00 ). This study is also supported by FWO Flanders grants ( 1.2.843.07.N.01, 1.5.244.05 to EDB and OZP 3G004306 to EDB and BPL) and Fund for Research in Ophthalmology ( FRO 2008 ). The project was supported with a grant ( UL1-RR-024134 ) from the National Center for Research Resources . KAH and ES are investigators at the Howard Hughes Medical Institute. We are indebted to the patients and their families for their continuous support of the study; to the medical, operating room, anaesthesia, and nursing staff at CHOP; and physicians and staff in the Division of Ophthalmology at CHOP. We give special thanks to Michael Ward, Laureen Murphy Kotzer, and Ivy Kuhn, for their clinical expertise. We thank the members of the CHOP institutional review board and their chairperson Mark Schreiner, and David Brint, Richard Hurwitz, Mark Blumenkranz, and David Birch for their invaluable guidance; and Edward Pugh Jr, Valder Arruda, Elias Traboulsi, Robert Nelson, Andrea Ballabio, and Alfredo Ciccodicola for helpful discussions. We thank Stuart Fine and Monte Mills for their support; and John Andrews-Labenski, Fred Letterio, Sohani Amarasekera, Karly Brint, Mohammed Toure, Nicholas Volpe Jr, Kalyani Bhatt, Daniel Bennett, Michael Bennett, Mettine H A Bos, William Bennett, Carmela Ziviello, Armida Faella, Anna Nesti, Angelo Torre, Sonali Joyce, Vito de Novellis, Ida Marabese, Liza Africa, Jitin Bajaj, Gary Pien, and Valentina Di Iorio for technical and clinical assistance; and Katherine H Maguire for editing the videos. The content of this report is solely the responsibility of the authors and does not necessarily represent the views of the funding sources, National Center for Research Resources, or the National Institutes of Health (both Bethesda, MD, USA).
PY - 2009
Y1 - 2009
N2 - Background: Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. Methods: We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. Findings: AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. Interpretation: The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Funding: Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.
AB - Background: Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. Methods: We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. Findings: AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. Interpretation: The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Funding: Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.
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U2 - 10.1016/S0140-6736(09)61836-5
DO - 10.1016/S0140-6736(09)61836-5
M3 - Article
C2 - 19854499
AN - SCOPUS:70350620424
SN - 0140-6736
VL - 374
SP - 1597
EP - 1605
JO - The Lancet
JF - The Lancet
IS - 9701
ER -