Purchase this article with an account.
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.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
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).
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.
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.
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.
This PDF is available to Subscribers Only