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Clinical Trial
. 2025 Oct 1;33(10):4784-4798.
doi: 10.1016/j.ymthe.2025.06.035. Epub 2025 Jul 1.

Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: One-year results of a phase I/II trial

Tomas S Aleman  1 , Katherine E Uyhazi  2 , Alejandro J Roman  2 , Mariejel L Weber  2 , Erin C O'Neil  3 , Malgorzata Swider  2 , Alexander Sumaroka  2 , Katherine H Maguire  2 , Elena M Aleman  2 , Arlene J Santos  2 , Rebecca J Kim  2 , Kelsey M Parchinski  2 , Andrew Billek  2 , Makayla Fradin  2 , William Chung  2 , Paris Margaritis  2 , Junwei Sun  4 , Drew H Scoles  3 , Vivian Wu  2 , Alexandra V Garafalo  2 , Ashwath Jayagopal  5 , Ben Yerxa  5 , Sarah Tuller  5 , Albert M Maguire  3 , Jean Bennett  2 , Artur V Cideciyan  2
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Free article
Clinical Trial

Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: One-year results of a phase I/II trial

Tomas S Aleman et al. Mol Ther. .
Free article

Abstract

We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness. This phase 1b/2a trial (NCT05616793) is a nonrandomized, single ascending, dose-escalation study. Three subjects with LCA5-LCA (ages 19, 26, and 34 years old) received uniocular subretinal injections of 1E10 vector genome per eye of OPGx-001. There were no serious adverse events related to OPGx-001 or the procedure. Retinal microstructure by spectral-domain optical coherence tomography showed no major changes in retinal lamination of the treated central retina compared with the contralateral control. Efficacy was detectable in these severely affected patients by subjective and objective methods at 1-month post-treatment and persisted for at least 12 months. Chromatic full-field stimulus testing showed improvements in cone-mediated vision averaging ∼1 log10 unit. Objective pupillometry confirmed perceptual results. Improvements were associated with better performance on a virtual reality orientation and mobility test. Visual acuity returned to baseline or improved in the treated eyes of all participants. The favorable safety profile and efficacy outcomes pave the path for enrolling milder phenotypes with careful dose escalation.

Keywords: AAV8; LCA5; Leber congenital amaurosis; Lebercilin.

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Conflict of interest statement

Declaration of interests J.B. is a scientific (non-equity-holding) founder of Spark Therapeutics and Opus Genetics, and founder of GenSight Biologics and Limelight Bio. She serves on scientific advisory boards for Akouos and Odylia Therapeutics and is the Principal Investigator of a sponsored research agreement from Limelight Bio. J.B. is a coinventor on a patent for a method to treat or slow the development of blindness but waived any financial interest in this technology in 2002. J.B. is a co-inventor on several other patents related to retinal gene therapy applications: 10,155,794; 9,567,376; 9,433,688; 9,249,425; 9,896,665; 8,147,823; 5,012,815; 20180369415; 20180369412; 20180153962; 20170319058; 201700143505; and 20160263246. T.S.A., J.B., and E.M.A. are co-authors on intellectual property (patent pending) through the University of Pennsylvania for the development of a virtual reality test used in this work.

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