Maria A Parker1, Laura R Erker1, Isabelle Audo2, Dongseok Choi3, Saddek Mohand-Said2, Kastytis Sestakauskas4, Patrick Benoit4, Terence Appelqvist5, Melissa Krahmer1, Caroline Ségaut-Prévost4, Brandon J Lujan1, Ambar Faridi6, Elvira N Chegarnov1, Peter N Steinkamp1, Cristy Ku1, Mariana Matioli da Palma1, Pierre-Olivier Barale2, Sarah Ayelo-Scheer2, Andreas Lauer1, Tim Stout7, David J Wilson1, Richard G Weleber1, Mark E Pennesi1, José Alain Sahel8, Paul Yang9. 1. From the Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA (M.A.P., L.R.E., D.C., M.K., B.J.L., A.F., E.N.C., P.N.S., C.K., M.M.D., A.L., D.J.W., R.G.W., M.E.P., P.Y.). 2. INSERM, CNRS, Institut de la Vision, Sorborne Université, Paris, France (I.A., S.M.-S., P.O.-B., S.A.-S., J.A.S.). 3. From the Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA (M.A.P., L.R.E., D.C., M.K., B.J.L., A.F., E.N.C., P.N.S., C.K., M.M.D., A.L., D.J.W., R.G.W., M.E.P., P.Y.); OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, Oregon, USA (D.C.). 4. Sanofi R&D, TA MS, Neurology, Ophthalmology and Gene Therapy Development, France (K.S., P.B., C.S.-P.). 5. Sanofi R&D, Translational Medicine and Early Development, Chilly-Mazarin (T.A.), France. 6. From the Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA (M.A.P., L.R.E., D.C., M.K., B.J.L., A.F., E.N.C., P.N.S., C.K., M.M.D., A.L., D.J.W., R.G.W., M.E.P., P.Y.); Veterans Affairs Portland Health Care System, Portland, Oregon (A.F.). 7. Cullen Eye Institute, Baylor College of Medicine, Houston, Texas (T.S.), USA. 8. INSERM, CNRS, Institut de la Vision, Sorborne Université, Paris, France (I.A., S.M.-S., P.O.-B., S.A.-S., J.A.S.); Centre d'Investigation Clinique, Inserm-DGOS 1423, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France (J.A.S.); Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA (J.A.S.). Electronic address: sahelja@upmc.edu. 9. From the Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA (M.A.P., L.R.E., D.C., M.K., B.J.L., A.F., E.N.C., P.N.S., C.K., M.M.D., A.L., D.J.W., R.G.W., M.E.P., P.Y.). Electronic address: yangp@ohsu.edu.
Abstract
PURPOSE: To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to mutations in ABCA4. DESIGN: Nonrandomized multicenter phase I/IIa clinical trial. METHODS: Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment. MAIN OUTCOME MEASURES: The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography. RESULTS: The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment. CONCLUSIONS: Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.
PURPOSE: To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to mutations in ABCA4. DESIGN: Nonrandomized multicenter phase I/IIa clinical trial. METHODS: Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment. MAIN OUTCOME MEASURES: The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography. RESULTS: The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment. CONCLUSIONS: Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.
Authors: K Mitrophanous; S Yoon; J Rohll; D Patil; F Wilkes; V Kim; S Kingsman; A Kingsman; N Mazarakis Journal: Gene Ther Date: 1999-11 Impact factor: 5.250
Authors: Katie Binley; Peter Widdowson; Julie Loader; Michelle Kelleher; Sharifah Iqball; Georgina Ferrige; Jackie de Belin; Marie Carlucci; Diana Angell-Manning; Felicity Hurst; Scott Ellis; James Miskin; Alcides Fernandes; Paul Wong; Rando Allikmets; Christopher Bergstrom; Thomas Aaberg; Jiong Yan; Jian Kong; Peter Gouras; Annick Prefontaine; Mark Vezina; Martin Bussieres; Stuart Naylor; Kyriacos A Mitrophanous Journal: Invest Ophthalmol Vis Sci Date: 2013-06-12 Impact factor: 4.799
Authors: Jean Bennett; Jennifer Wellman; Kathleen A Marshall; Sarah McCague; Manzar Ashtari; Julie DiStefano-Pappas; Okan U Elci; Daniel C Chung; Junwei Sun; J Fraser Wright; Dominique R Cross; Puya Aravand; Laura L Cyckowski; Jeannette L Bennicelli; Federico Mingozzi; Alberto Auricchio; Eric A Pierce; Jason Ruggiero; Bart P Leroy; Francesca Simonelli; Katherine A High; Albert M Maguire Journal: Lancet Date: 2016-06-30 Impact factor: 79.321