July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Vector shedding and immunology results from a gene therapy clinical trial for choroideremia
Author Affiliations & Notes
  • Alun R Barnard
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, United Kingdom
  • Anna Rudenko
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, United Kingdom
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
  • Kanmin Xue
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, United Kingdom
  • Robert E MacLaren
    Nuffield Lab of Ophthalmology, University of Oxford, Oxford, ENGLAND, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust and NIHR Biomedical Research Centre, Oxford, United Kingdom
  • Footnotes
    Commercial Relationships   Alun Barnard, University of Oxford (E); Anna Rudenko, None; Kanmin Xue, None; Robert MacLaren, Choroideremia Research Foundation (F), Euretina (S), Nightstar Therapeutics Inc (I), Nightstar Therapeutics Inc (C), Nightstar Therapeutics Inc (P), Nightstar Therapeutics Inc (F), Nightstar Therapeutics Inc (E), Spark Therapeutics Inc (C), University of Oxford (E), University of Oxford (P)
  • Footnotes
    Support  The clinical trial was funded by the Health Innovation Challenge Fund (HICF-1009-006), a parallel funding partnership between the Wellcome Trust and the UK Department of Health. Additional funding was provided from the Health Foundation, Fight for Sight, the Lanvern Foundation, the Special Trustees of Moorfields Eye Hospital, the Royal College of Surgeons of Edinburgh, the NIHR Biomedical Research Centres at the Oxford University Hospitals and Moorfields Eye Hospital NHS Trusts.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5654. doi:
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    • Get Citation

      Alun R Barnard, Anna Rudenko, Kanmin Xue, Robert E MacLaren; Vector shedding and immunology results from a gene therapy clinical trial for choroideremia. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5654.

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Abstract

Purpose : Assessing the safety profile of gene therapy treatment often involves monitoring for systemic immunological responses to the delivery of the vector and gathering data on how vector disseminates into the environment through secretions and/or excreta of the patient (defined as vector shedding). We report here on vector shedding and systemic immune responses in 5 patients who received subretinal injection of an AAV-based vector (1E+11 genome particles) as part of a clinical trial of gene therapy for choroideremia (ClinicalTrials.gov Identifier: NCT01461213).

Methods : Samples were collected at pre-operative baseline, 1 day, 1 week, 1 month, 3 months and 6 months post-surgery. Samples of saliva, urine, blood, and tears were collected and assessed for the presence of AAV-genomes by quantitative PCR analysis (limit of detection: 50 genomes per 5 µl). Blood samples were also collected for isolation of the serum fraction. These samples were assessed for systemic immune responses by analysing for the presence of neutralising antibodies against AAV2 using an in vitro reporter system.

Results : A positive vector shedding result was found in 1 patient, in the tear sample collected from the treated eye on the day immediately following surgery (920.9 genomes in 5 µl). All other samples and timepoints for this patient were negative, as were all from the other patients, suggesting vector shedding after subretinal delivery is very limited. The levels of neutralising, Anti-AAV2 antibodies in serum samples were low in all 5 patients at baseline (titre <10). Importantly, these did not rise after treatment with the vector and remained <10 throughout the follow-up period, indicating that no significant immunological responses were elicited in response to delivery of the gene therapy (AAV.REP1) vector at this dose.

Conclusions : Our results are similar to others, which have shown very limited vector shedding and a lack of clinically meaningful systemic responses to the small AAV2 doses and subretinal administration commonly used in retinal gene therapy.These tests can be unpleasant for patients and are time consuming for the study teams. There is, therefore, a good argument for modifying current guidelines to acknowledge clear differences depending on the route of administration of gene therapy products, with a possibility of eliminating at least some of these tests from future clinical studies.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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