Edinburgh Research Explorer

Participant : 15th Annual Meeting of the American Society for Gene and Cell Therapy

Activity: Participating in or organising an event typesParticipation in conference


TOXICOLOGY STUDIES IN SUPPORT OF THE UK CF GENE THERAPY CONSORTIUM’S MULTI-DOSE CLINICAL TRIAL G McLachlan, U Griesenbach, D Collie, JA Innes, T Higgins, S Cheng, R Scheule, EWFW Alton, JC Davies, SC Hyde, DR Gill, D Porteous, AC Boyd on behalf of the UK CF Gene Therapy Consortium Imperial College London, University of Edinburgh, University of Oxford Genzyme In preparation for a Multi-dose clinical trial to assess whether 12 monthly doses of the CFTR gene can improve CF lung disease we have conducted two toxicology studies (TS). In addition to a GLP-mouse TS study (outsourced to a CRO) we also performed an in-house study in sheep. Mice received 12 doses of pGM169 (a plasmid carrying the CFTR gene) complexed to Genzyme lipid GL67A at fortnightly intervals by inhalation; exposure to the complex was for 0.5 (low= ~5x human dose), 2 (mid= ~ 20x human dose) or 6 hr (high dose=~60x human dose). Controls were exposed to air for 6 hr. Standard non-invasive assessments at regular intervals and post-mortem toxicology were undertaken 2 weeks and 3 months after the last dose. Approximately 600 mice were included in the study. Anesthetised sheep (n=8) received 9 doses (consistent with EMEA guidelines) of aerosolized pGM169/GL67A at monthly intervals. Similar assessments were made as for the mouse TS, in addition to lung function measurements and bronchoalveolar lavage (BAL) at intervals throughout the study. The amount (mg/kg) of pGM169/GL67A delivered to sheep approximately mimics the proposed human dose. Anesthetised controls (n=8) received air only. Results: All mice tolerated the treatment well. In the high dose group (~60x human dose) small increases in lung weight and circulating neutrophils were seen 2 days after the last dose, but not in the cohort sacrificed 14 days after the last dose. Histology showed scattered alveolar macrophages in the low and mid dose groups 2 weeks after administration of the last dose. In the high dose group multifocal alveolar foamy macrophage accumulations and occasional inflammation were noted. The presence of fat in macrophages was confirmed by Oil Red O staining. There was no evidence of structural remodelling. All other organs were unremarkable. 3 months after administration, findings in the low dose were not different from baseline, but were still observed in the mid and high dose. All sheep tolerated treatment well. In contrast to mice, haematology 1 or 15 days after dosing did not show any treatment related effects. Neutrophils were transiently increased in BAL fluid 1 day after administration, but had returned to baseline after 15 days. Observed changes in lung function or gas transfer measurements were mild and not test item related. There were no test item related histological findings in any organ. Conclusions: All animals tolerated the treatment well. The transient and dose-related systemic inflammatory responses and drop in lung function observed in the single-dose phase 1 trial were not replicated in non-CF sheep and non-CF mice only developed mild systemic inflammation at the highest dose (~50x human dose) possibly highlighting species-specific differences or an increased response to the lipid/DNA complexes in the inflamed human CF lung. Both TS support progression into a Multi-dose CF gene therapy trial.

Attending event

15th Annual Meeting of the American Society for Gene and Cell Therapy

Duration15 May 201219 May 2012
CountryUnited States

Event: Conference

ID: 7568076