Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.
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Maguire Albert M, High Katherine A, Auricchio Alberto, Wright J Fraser, Pierce Eric A, Testa Francesco, Mingozzi Federico, Bennicelli Jeannette L, Ying Gui-shuang, Rossi Settimio, Fulton Ann, Marshall Kathleen A, Banfi Sandro, Chung Daniel C, Morgan Jessica I W, Hauck Bernd, Zelenaia Olga, Zhu Xiaosong, Raffini Leslie, Coppieters Frauke, De Baere Elfride, Shindler Kenneth S, Volpe Nicholas J, Surace Enrico M, Acerra Carmela, Lyubarsky Arkady, Redmond T Michael, Stone Edwin, Sun Junwei, McDonnell Jennifer Wellman, Leroy Bart P, Simonelli Francesca, Bennett Jean
Аннотация
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 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) 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.