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Three-Year Safety Results of SAR422459 (EIAV-ABCA4) Gene Therapy in Patients With ABCA4-Associated Stargardt Disease: An Open-Label Dose-Escalation Phase I/IIa Clinical Trial, Cohorts 1-5.
Parker, Maria A; Erker, Laura R; Audo, Isabelle; Choi, Dongseok; Mohand-Said, Saddek; Sestakauskas, Kastytis; Benoit, Patrick; Appelqvist, Terence; Krahmer, Melissa; Ségaut-Prévost, Caroline; Lujan, Brandon J; Faridi, Ambar; Chegarnov, Elvira N; Steinkamp, Peter N; Ku, Cristy; da Palma, Mariana Matioli; Barale, Pierre-Olivier; Ayelo-Scheer, Sarah; Lauer, Andreas; Stout, Tim; Wilson, David J; Weleber, Richard G; Pennesi, Mark E; Sahel, José Alain; Yang, Paul.
Afiliação
  • Parker MA; 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.).
  • Erker LR; 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.).
  • Audo I; INSERM, CNRS, Institut de la Vision, Sorborne Université, Paris, France (I.A., S.M.-S., P.O.-B., S.A.-S., J.A.S.).
  • Choi D; 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
  • Mohand-Said S; INSERM, CNRS, Institut de la Vision, Sorborne Université, Paris, France (I.A., S.M.-S., P.O.-B., S.A.-S., J.A.S.).
  • Sestakauskas K; Sanofi R&D, TA MS, Neurology, Ophthalmology and Gene Therapy Development, France (K.S., P.B., C.S.-P.).
  • Benoit P; Sanofi R&D, TA MS, Neurology, Ophthalmology and Gene Therapy Development, France (K.S., P.B., C.S.-P.).
  • Appelqvist T; Sanofi R&D, Translational Medicine and Early Development, Chilly-Mazarin (T.A.), France.
  • Krahmer M; 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.).
  • Ségaut-Prévost C; Sanofi R&D, TA MS, Neurology, Ophthalmology and Gene Therapy Development, France (K.S., P.B., C.S.-P.).
  • Lujan BJ; 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.).
  • Faridi A; 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.).
  • Chegarnov EN; 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.).
  • Steinkamp PN; 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.).
  • Ku C; 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.).
  • da Palma MM; 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.).
  • Barale PO; INSERM, CNRS, Institut de la Vision, Sorborne Université, Paris, France (I.A., S.M.-S., P.O.-B., S.A.-S., J.A.S.).
  • Ayelo-Scheer S; INSERM, CNRS, Institut de la Vision, Sorborne Université, Paris, France (I.A., S.M.-S., P.O.-B., S.A.-S., J.A.S.).
  • Lauer A; 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.).
  • Stout T; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas (T.S.), USA.
  • Wilson DJ; 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.).
  • Weleber RG; 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.).
  • Pennesi ME; 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.).
  • Sahel JA; 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 Pitt
  • Yang P; 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.
Am J Ophthalmol ; 240: 285-301, 2022 08.
Article em En | MEDLINE | ID: mdl-35248547
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Terapia Genética / Doença de Stargardt Tipo de estudo: Clinical_trials / Risk_factors_studies Limite: Humans Idioma: En Revista: Am J Ophthalmol Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Terapia Genética / Doença de Stargardt Tipo de estudo: Clinical_trials / Risk_factors_studies Limite: Humans Idioma: En Revista: Am J Ophthalmol Ano de publicação: 2022 Tipo de documento: Article