{
  "abstract": "Purpose PDE6A-associated retinitis pigmentosa (RP) is a rare inherited retinal disease leading to severe vision loss and blindness, with no available treatment. This study assessed the safety and vision outcomes of a gene therapy using an adeno-associated virus (AAV) vector encoding PDE6A (AAV8.hPDE6A).Methods In an open-label, non-randomised controlled phase I/IIa trial, nine patients with biallelic PDE6A variants received a single subretinal injection of AAV8.hPDE6A. Doses were either 1.0×10¹⁰ (n=6) or 5.0×10¹⁰ (n=3) total vector genomes. Safety was the primary endpoint, assessed via clinical examinations, laboratory analyses and optical coherence tomography imaging. Secondary outcomes included changes in visual function, such as best corrected visual acuity (BCVA), contrast sensitivity, colour perception, dark adaptation thresholds, visual fields, patient-reported outcomes and chromatic pupil campimetry over 1 year.Results The mean patient age was 40.1 years, with baseline BCVA ranging from 40 to 82 letters (0.9–0.1 logMAR). No systemic adverse events occurred, and most ocular events resolved without treatment. Persistent adverse events included small peripheral atrophic areas (n=2), disturbed colour discrimination (n=3), cataract (n=1), slight central retinal thinning (n=5) and moderate visual acuity loss (n=2, 1 in each dose group). BCVA, full-field stimulus thresholds and other visual function measures showed statistically non-significant changes, with a trend towards worsening of retinal sensitivity in the treated eyes.Conclusion Subretinal gene therapy with AAV8.hPDE6A did not improve visual function over 1 year and posed risks, including central retinal thinning and visual acuity decline. This is in contrast to the safety and efficacy profile established in preclinical models.",
  "authors": [
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany",
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Felix F Reichel"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany",
        "Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK"
      ],
      "name": "M Dominik Fischer"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany",
        "Centre for Rare Eye Diseases, University of Tübingen, Tübingen, Germany"
      ],
      "name": "Katarina Stingl"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Laura Kuehlewein"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany",
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Immanuel Seitz"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Tobias Peters"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Melanie Ziegler"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Barbara Wilhelm"
    },
    {
      "affiliations": [
        "Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Susanne Kohl"
    },
    {
      "affiliations": [
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Nicole Weisschuh"
    },
    {
      "affiliations": [
        "Institute of Clinical Epidemiology and Applied Biometrics, University of Tübingen, Tübingen, Germany"
      ],
      "name": "Peter Martus"
    },
    {
      "affiliations": [
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Mathias Seeliger"
    },
    {
      "affiliations": [
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Regine Muehlfriedel"
    },
    {
      "affiliations": [
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Francois Paquet-Durand"
    },
    {
      "affiliations": [
        "Department of Ophthalmology, Columbia University, New York, NY, USA"
      ],
      "name": "Stephen H Tsang"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Karl Ulrich Bartz-Schmidt"
    },
    {
      "affiliations": [
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Marius Ueffing"
    },
    {
      "affiliations": [
        "University Eye Hospital, Centre for Ophthalmology, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Eberhart Zrenner"
    },
    {
      "affiliations": [
        "Department of Pharmacy, Center for Drug Research, LMU Munich, Munich, Germany"
      ],
      "name": "Martin Biel"
    },
    {
      "affiliations": [
        "Institute for Ophthalmic Research, Centre for Ophthalmology, Centre for Ophthalmology, University Hospital Tubingen, Tübingen, Germany"
      ],
      "name": "Bernd Wissinger"
    },
    {
      "affiliations": [
        "Department of Ophthalmology, LMU University Hospital, LMU Munich, Munich, Germany"
      ],
      "name": "Stylianos Michalakis"
    },
    {
      "affiliations": [],
      "name": "on behalf of the RD-Cure Consortium"
    }
  ],
  "title": "Safety and vision outcomes of subretinal gene supplementation therapy in PDE6A-associated retinitis pigmentosa: a non-randomised controlled trial",
  "uid": "40781c62-1679-5dc0-b37e-0fa27221926f"
}