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Elena Posse de Chaves, Sarah Samuelson, Diego Ordoñez, Qian Wang, Chris St. Laurent, Ian M MacDonald, Yves Sauve; Effect of Simvastatin on REP-1 Replacement Therapy in a Mouse Model of Choroideremia. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3395. doi: https://doi.org/.
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Based on a health survey on choroideremia (CHM) co-morbidities, we suggested that statin intake was associated with poorer vision. Statins inhibit HMG-CoA reductase, impeding isoprenoid synthesis and protein prenylation. In choroideremia, prenylation is already compromised by CHMmutations. Therefore, statins may not only exacerbate the deleterious outcome of loss of REP-1 but also preclude effective CHMgene replacement therapies by limiting the isoprenoid pool. We examined the effect of simvastatin on disease progression and on the efficacy of gene therapy in a mouse model of choroideremia.
One-month-old CHM Flox PGK1-Cre mice received a single subretinal injection of 1 µl of AAV2/2-CBA-REP1 containing 7X1011genome particles in both eyes, or of vehicle alone (sham). Micewere then randomly assigned to treatment with simvastatin diet (dietary intake of 100 mg/kg/day) or control diet, N= 20 per group. Intensity-series of dark- and light-adapted full field electroretinograms (ERGs) were recorded just before injection and 3, 5, and 7 months post-treatment. Optical coherence tomography (OCT) was performed after 1and 7 months of treatment. Mice were culled at 7 months. One eye was processed for histology, while the other was used to analyze Rab prenylation (Rab GDI capturing method), Rep-1 expression (western blotting) and simvastatin efficacy (qPCR to measure the expression level of the HMG-CoA reductase gene).
Subretinal injections of AAV2/2-CBA-REP1 into CHM mice resulted in REP-1 expression throughout RPE after 7 months of injection as detected by fluorescent microscopy in RPE flat mount preparations and by western blot analysis. Simvastatin did not affect REP-1 expression. REP-1expression slowed down retina damage in animals under the normal diet or with simvastatin as indicated by stabilization of a- and b-wave of ERG responses in comparison to sham-injected eyes.
These data indicated that the AAV2/2-CBA-REP1 virus used here provided suitable gene therapy for choroideremia and that simvastatin did not significantly alter efficacy of the treatment.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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