July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Preliminary results in 18 patients undergoing retinal gene therapy for X-linked retinitis pigmentosa with codon-optimized AAV8-RPGR
Author Affiliations & Notes
  • Robert E MacLaren
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
  • Janet L Davis
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Ninel Gregori
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Jasmina Cehajic-Kapetanovic
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
  • Byron L Lam
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Andrew Lotery
    University of Southampton, Southampton, United Kingdom
  • Cristina Martinez-Fernandez dela Camara
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
  • Anika Nanda
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
  • Anna Paola Salvetti
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
  • Paulo Stanga
    Manchester Royal Eye Hospital, United Kingdom
  • Kanmin Xue
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
  • Footnotes
    Commercial Relationships   Robert MacLaren, Nightstar Therapeutics (F), Nightstar Therapeutics (C), Nightstar Therapeutics (I), University of Oxford (P); Janet Davis, None; Ninel Gregori, Nightstar Therapeutics (F); Jasmina Cehajic-Kapetanovic, None; Byron Lam, Nightstar Therapeutics (F), Nightstar Therapeutics (C); Andrew Lotery, Nightstar Therapeutics (F); Cristina Martinez-Fernandez dela Camara, None; Anika Nanda, None; Anna Paola Salvetti, None; Paulo Stanga, Nightstar Therapeutics (F); Kanmin Xue, None
  • Footnotes
    Support  Nightstar Therapeutics
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1329. doi:https://doi.org/
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      Robert E MacLaren, Janet L Davis, Ninel Gregori, Jasmina Cehajic-Kapetanovic, Byron L Lam, Andrew Lotery, Cristina Martinez-Fernandez dela Camara, Anika Nanda, Anna Paola Salvetti, Paulo Stanga, Kanmin Xue; Preliminary results in 18 patients undergoing retinal gene therapy for X-linked retinitis pigmentosa with codon-optimized AAV8-RPGR. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1329. doi: https://doi.org/.

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

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Abstract

Purpose : To investigate the safety and efficacy of adeno-associated viral vector (AAV8) encoding retinitis pigmentosa GTPase regulator (RPGR) for X-linked retinitis pigmentosa (XLRP).

Methods : This study (ClinicalTrials.gov ID NCT03116113) is being conducted in 2 Parts: Part I is a Phase 1 dose-escalation study to identify the maximum tolerated dose (MTD); Part II is a Phase 2/3, assessor-masked, dose-expansion study. In Part I, subjects with genetically confirmed RPGR-associated XLRP were administered a sub-retinal dose of AAV8-RPGR. The vector used a rhodopsin kinase promoter to drive expression of a codon-optimized sequence that generated the correct full length RPGR protein. A 3+3 escalation scheme was used, with 3 subjects/dose (5×109, 1×1010, 5×1010, 1×1011, 2.5×1011, and 5×1011 gp). Part I endpoints were safety (adverse events [AEs], dose-limiting toxicities [DLTs], ophthalmic assessments, viral shedding and immunogenicity). Preliminary efficacy measures included retinal sensitivity via MAIA microperimetry.

Results : Part I enrollment has been completed and 1-month assessments are available on 18 male subjects (mean age 32.3±9.4 years). AAV8-RPGR was shown to be safe, with no occurrence of serious AEs or DLTs. In this ongoing study, 45 treatment-emergent events (TEAEs) have occurred in 15 subjects: 11 non-ocular and 34 ocular, 30 of which occurred in the study eye. No subjects have been withdrawn due to a TEAE.
Despite undergoing macular detachment, mean visual acuity recovered from 57.2±4.3 letters at baseline to 57.3±3.8 by month 1. Retinal sensitivity however improved (defined by gain of at least 7 dB in at least 5 loci) in 6 of the 18 treated eyes versus 1 untreated eye at Month 1. The largest gain was seen in a cohort 4 patient who went from 0.5 dB in his treated eye at baseline (untreated eye 0.7 dB) to 3.4 dB at month 1 (untreated eye 0.5 dB) and 6.6 dB at month 3 (untreated eye 0.5 dB). The patients with microperimetry gains also reported subjective visual field improvements in their treated eyes.

Conclusions : With a single dose of AAV8-RPGR, improvements in retinal sensitivity have been observed in XLRP patients. This unexpected finding may relate to improved cone function following successful delivery of the full length RPGR protein.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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