Investigative Ophthalmology & Visual Science Cover Image for Volume 65, Issue 7
June 2024
Volume 65, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2024
Efficacy and Safety of AAV-based LRAT Gene Supplementation Therapy in a New Lrat Rat Model for Retinitis Pigmentosa
Author Affiliations & Notes
  • Céline Koster
    Human Genetics, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
    Ophthalmology, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
  • Ardine de Vos
    Animal Research Institute AMC, Netherlands
  • Anna Maria El-Kalaani
    Human Genetics, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
  • Colby F. Lewallen
    National Eye Institute, Bethesda, Maryland, United States
  • Andrea Heredero
    Human Genetics, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
    Ophthalmology, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
  • Devin McDougald
    Biogen Inc, Cambridge, Massachusetts, United States
  • Nicolas Lonfat
    Biogen Inc, Cambridge, Massachusetts, United States
  • Kip M Connor
    Biogen Inc, Cambridge, Massachusetts, United States
  • Camiel Boon
    Ophthalmology, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
    Ophthalmology, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Arthur Bergen
    Human Genetics, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
    Ophthalmology, Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands
  • Footnotes
    Commercial Relationships   Céline Koster None; Ardine de Vos None; Anna El-Kalaani None; Colby Lewallen None; Andrea Heredero None; Devin McDougald None; Nicolas Lonfat None; Kip Connor None; Camiel Boon None; Arthur Bergen None
  • Footnotes
    Support  Health Holland TKI - PPP
Investigative Ophthalmology & Visual Science June 2024, Vol.65, 5343. doi:
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      Céline Koster, Ardine de Vos, Anna Maria El-Kalaani, Colby F. Lewallen, Andrea Heredero, Devin McDougald, Nicolas Lonfat, Kip M Connor, Camiel Boon, Arthur Bergen; Efficacy and Safety of AAV-based LRAT Gene Supplementation Therapy in a New Lrat Rat Model for Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2024;65(7):5343.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinitis pigmentosa (RP) is a progressive monogenic retinal disease, with concentric visual field loss, frequently leading to legal blindness. The prevalence of RP is roughly 1:3,500. The age at onset is generally within the first decades of life having a massive impact on the quality of life. Except for one sub-group of retinal dystrophy patients, those having mutations in the RPE65 gene, no therapies are available to stop the disease’s progression and prevent blindness in RP. In this study, we aim to test the efficacy and safety of adeno-associated virus (AAV)-based gene supplementation therapy in a new rat model for the LRAT-RP subtype. Biochemically, LRAT is the precursor of RPE65 in the visual cycle, which makes gene therapy for this subtype of RP feasible.

Methods : Five-week-old Lrat deficient rats (Lrat-/-, Brown Norway (BN) background) and wildtype BN rats were injected subretinally (2 or 3 µL) with AAVs containing the human LRAT gene, the EGFP gene or both LRAT and EGFP genes, using a range of viral doses (3E8 – 3E10 viral genomes/eye). The rats were non-invasively followed up for eight weeks post-injection using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), electroretinography (ERG) as well as vision-based behavioral assays. At the end of the experiment, the rats were sacrificed and the eyes were harvested for additional histological, RNA, and protein analyses.

Results : AAVs containing the human LRAT gene were successfully delivered in the subretinal space of Lrat-/- rats. Based on SLO, OCT, ERG, and vision-based behavioral data, the higher doses caused toxicity at and surrounding the injection site. The medium and lower doses did not show any detectable toxicity. Based on the EGFP fluorescence, detected by SLO, the expression of the supplemented gene(s) spread far beyond the injection site. In Lrat-/- rats treated with gene supplementation therapy improvements could be observed based on OCT, ERG, and histological data when compared to untreated or sham-injected Lrat-/- rats.

Conclusions : An AAV containing the human LRAT cDNA was successfully delivered in Lrat-/- rats. The functional and structural retinal changes following injection were determined non-invasively. LRAT gene supplementation therapy, injected in the subretinal space of Lrat-/- rats, shows potential as an experimental therapy for LRAT-based RP.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

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