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- W3085838742 abstract "<h3>Introduction</h3> We have developed a Simian Immunodeficiency Virus (SIV)-based lentiviral vector pseudotyped with the Sendai-virus envelope glycoproteins (F/HN) (rSIV.F/HN) that is effective at transducing pulmonary epithelium <i>in vivo</i>. To prepare for a first-in-man clinical trial, we have developed protocols that can be used in a mouse GLP-toxicology study to efficiently transduce nasal-tissue or lungs. <h3>Methods</h3> Reporter-imaging, molecular, and radiopharmaceutical tracing methods have been used to quantify intranasally administered lentiviral vector deposition and subsequent tissue-level transgene expression in mice. <h3>Results</h3> Nose study. A standard 100 µL vector bolus administration (‘nasal sniffing’) was compared to slow perfusion via catheter (6.7µL/min) and to small volume pipette dosing (2 × 5µL). All animals received 1e7 TU/mouse of rSIV.F/HN expressing luciferase (n=6/group). 10–12 days after transduction, all methods led to similar gene expression in the nasal cavity. Catheter-based delivery led to significant (p<0.05) spill-over into the lung and was discontinued. In contrast to nasal sniffing, pipetting of small volumes abrogated lung transgene expression. Technetium radiotracer (5MBq of <sup>99m</sup>Tc-DTPA/mouse) showed that 98±1% of the pipetted dose was retained in the head. In contrast, nasal sniffing retained only 36±12% in the head, with the rest dispersed into lungs (34±16%) and the remaining body (30±5%). To increase vector delivery to the nasal epithelium, 5 and 10 × 5µL doses (at 5 min intervals) were administered, up to 2.4e8 TU/mouse (n=5/group), and a dose-related increase in gene expression was observed (P<0.0001, r<sup>2</sup>=0.87). Importantly, even after 10 × 5µL doses, most radiotracer (90±3%) was retained in the head. Lung study. Comparing nasal sniffing to an oropharyngeal (OP) delivery method (1e7 TU/50µL dose for both techniques), there was no difference in gene expression between lungs. By technetium radiotracer (5MBq as before, n=5–6/group), there was no difference in dose distribution between lungs (sniffing: 40±18%, OP: 37±11%). However, nasal sniffing can deliver double the volume compared to OP. <h3>Conclusions</h3> To optimise target organ vector delivery, we have developed protocols suitable for GLP toxicology studies in the murine nose and lung. By defining dose distribution, effective viral titres and overages can be better calculated and compared to proposed clinical doses in future toxicology studies." @default.
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- W3085838742 date "2021-01-21" @default.
- W3085838742 modified "2023-10-14" @default.
- W3085838742 title "S52 Development of protocols for mouse GLP-toxicology studies" @default.
- W3085838742 doi "https://doi.org/10.1136/thorax-2020-btsabstracts.57" @default.
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