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Biodistribution of adeno-associated virus type 2 carrying multi-characteristic opsin in dogs following intravitreal injection.

ABSTRACT: Gene therapy of retinal diseases using recombinant adeno-associated virus (rAAV) vector-based delivery has shown clinical success, and clinical trials based on rAAV-based optogenetic therapies are currently in progress. Recently, we have developed multi-characteristic opsin (MCO), which has been shown to effectively re-photosensitize photoreceptor-degenerated retina in mice leading to vision restoration at ambient light environment. Here, we report the biodistribution of the rAAV2 carried MCO (vMCO-I) in live samples and post-mortem organs following intraocular delivery in wild-type dogs. Immunohistochemistry showed that the intravitreal injection of vMCO-I resulted in gene transduction in the inner nuclear layer (INL) but did not induce detectable inflammatory or immune reaction in the dog retina. Vector DNA analysis of live body wastes and body fluids such as saliva and nasal secretions using quantitative polymerase chain reaction (qPCR) showed no correlative increase of vector copy in nasal secretions or saliva, minimal increase of vector copy in urine in the low-dose group 13 weeks after injection and in the faeces of the high-dose group at 3-13 weeks after injection suggesting clearance of the virus vector via urine and faeces. Further analysis of vector DNA extracted from faeces using PCR showed no transgene after 3 weeks post-injection. Intravitreal injection of vMCO-I resulted in few sporadic off-target presences of the vector in the mesenteric lymph node, liver, spleen and testis. This study showed that intravitreal rAAV2-based delivery of MCO-I for retinal gene therapy is safe.

SUBMITTER: Tchedre KT

PROVIDER: S-EPMC8435460 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceDespite the unquestionable effectiveness of anti-vascular endothelial growth factor therapy (VEGF), there is ongoing controversy about potential systemic adverse effects. Besides the direct adverse effects of anti-VEGF agents, other factors associated with the injection itself, such as perioperative blood pressure fluctuations, may contribute to adverse events.ObjectiveTo determine blood pressure fluctuations during intravitreal injections.Design, setting, and participantsProspective observational study at a tertiary referral center (Department of Ophthalmology, University Hospital Bern, Bern, Switzerland). Consecutive patients scheduled for intravitreal injections were recruited. Data were analyzed between October 2017 and January 2018.Main outcomes and measuresSystolic and diastolic blood pressure, pulse rate, and oxygen saturation were recorded before, during, and after the intravitreal injection. An anxiety questionnaire was completed by all participants. Multivariate regression analysis was used to investigate potential factors associated with blood pressure rise during injections.ResultsTwo hundred one patients (92 women and 109 men) were included in this study, with a mean age of 68 years (range, 18-93 years). Mean (SD) systolic blood pressure increased from a baseline of 150 (20) mm Hg to 162 (24) mm Hg following the preparation procedure to 168 (24) mm Hg during the injection (P < .001). Mean (SD) diastolic blood pressure increased from 78 (14) mm Hg to 83 (37) mm Hg to 83 (16) mm Hg, respectively (P = .009). Mean (SD) pulse frequency increased from 76 (13) bpm to 80 (13) bpm (P = .005). In total, 23 patients (11%) had a systolic blood pressure greater than 200 mm Hg. This subgroup of patients had a mean (SD) perioperative systolic blood pressure increase from 182 (19) mm Hg to 214 (12) mm Hg, resulting in an increase of 32 (20) mm Hg (P < .001). Age and anxiety were to be next associated with systolic blood pressure rise.Conclusions and relevanceThe intravitreal injection process is associated with a transient increase in blood pressure. Most of the increase occurs following the preparation before the injection itself. This may constitute a risk factor for cardiovascular or cerebrovascular complications during treatment and could be of particular relevance in patients at high risk for such events and those receiving frequent injections. Future work may be needed to determine whether, in patients at risk for cardiovascular or cerebrovascular events, perioperative blood pressure monitoring or antihypertensive therapy needs to be considered.

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Biodistribution of adeno-associated virus type 2 carrying multi-characteristic opsin in dogs following intravitreal injection.

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