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Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial
Journal article   Open access   Peer reviewed

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, …
The Lancet (British edition), Vol.374(9701), pp.1597-1605
11/07/2009
DOI: 10.1016/S0140-6736(09)61836-5
PMCID: PMC4492302
PMID: 19854499
url
https://doi.org/10.1016/S0140-6736(09)61836-5View
Published (Version of record) Open Access

Abstract

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. 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. 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. 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. 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.
 Safety Dependovirus - genetics Nystagmus, Physiologic Age Factors Humans Male Optic Atrophy, Hereditary, Leber - genetics Genetic Vectors - therapeutic use Dark Adaptation Dose-Response Relationship, Drug Young Adult Adult Female Blindness - congenital Eye Proteins - genetics Optic Atrophy, Hereditary, Leber - diagnosis Child cis-trans-Isomerases Electroretinography Treatment Outcome Optic Atrophy, Hereditary, Leber - therapy Mutation - genetics Visual Acuity Blindness - genetics Disease Progression Genetic Vectors - genetics Carrier Proteins - genetics Injections Adolescent Genetic Therapy - methods

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