Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial

Albert M. Maguire, Katherine A. High, Alberto Auricchio, J. Fraser Wright, Eric A. Pierce, Francesco Testa, Federico Mingozzi, Jeannette L. Bennicelli, Gui shuang Ying, Settimio Rossi, Ann Fulton, Kathleen A. Marshall, Sandro Banfi, Daniel C. Chung, Jessica IW Morgan, Bernd Hauck, Olga Zelenaia, Xiaosong Zhu, Leslie Raffini, Frauke CoppietersElfride De Baere, Kenneth S. Shindler, Nicholas J. Volpe, Enrico M. Surace, Carmela Acerra, Arkady Lyubarsky, T. Michael Redmond, Edwin Stone, Junwei Sun, Jennifer Wellman McDonnell, Bart P. Leroy, Francesca Simonelli, Jean Bennett*

*Corresponding author for this work

Research output: Contribution to journalArticle

573 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1597-1605
Number of pages9
JournalThe Lancet
Volume374
Issue number9701
DOIs
StatePublished - Jan 1 2009

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ASJC Scopus subject areas

  • Medicine(all)

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Maguire, A. M., High, K. A., Auricchio, A., Wright, J. F., Pierce, E. A., Testa, F., Mingozzi, F., Bennicelli, J. L., Ying, G. S., Rossi, S., Fulton, A., Marshall, K. A., Banfi, S., Chung, D. C., Morgan, J. IW., Hauck, B., Zelenaia, O., Zhu, X., Raffini, L., ... Bennett, J. (2009). Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. The Lancet, 374(9701), 1597-1605. https://doi.org/10.1016/S0140-6736(09)61836-5