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Tomas S Aleman, Rachel M Huckfeldt, Leona Serrano, Grace Vergilio, Denise J Pearson, Katherine E. Uyhazi, Sarah McCague, Kathleen Marshall, Daniel C Chung, Emily Liu, Eric A Pierce, Jessica Ijams Wolfing Morgan, Jean Bennett, Dean Eliott, Jason Comander, Albert M. Maguire; AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: 2 year Results of an Ongoing Phase I/II Gene Therapy Trial. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5173. doi: https://doi.org/.
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To assess preliminary safety and efficacy data of the investigational subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human REP1-encoding cDNA in choroideremia (CHM).
Ten subjects with CHM (ages 26-57 years at injection), received uniocular subfoveal injections of low dose (up to 5x1010 vector genome (vg) per eye, n=5) or high dose (up to 1x1011 vg per eye, n=5) AAV2-hCHM. Patients were evaluated pre- and post-operatively at study-defined follow up visits for 2 years. Ocular safety was assessed by ophthalmic examination, perimetry, spectral domain optical coherence tomography (SD-OCT) and short-wavelength autofluorescence (SW-FAF) and by conventional automated perimetry and microperimetry.
There were no surgery-related complications or unexpected adverse events. By two years visual acuity (VA) returned to baseline in all but one patient who slowly recovered to -17 letters of baseline. With the exclusion of this patient, mean VA letter counts differences (2 year minus baseline) were similar in injected (-1.7 letters) compared to uninjected (-0.3 letters) eyes. Two patients showed greater VA counts (5-6 letters) in the injected eye compared to baseline and to the uninjected control. Mean sensitivity by microperimetry changed minimally in injected (mean±SD=-0.7±0.75dB) and uninjected (-0.3±0.59 dB) eyes. There were no significant differences between injected and uninjected eyes in absolute dark-adapted cone-mediated sensitivities at the fovea or within the central 30° of eccentricity. There was a slightly slower mean rate of reduction of the IS/OS band horizontal extent in injected eyes (-69±59μm/year) compared to uninjected eyes (-96±67μm/year), which corresponded in extent to the areas of SW-FAF. There were no obvious dose-dependent relationships.
VA in 9/10 subjects was unchanged (less than ±10 letters difference from baseline) after the subfoveal injections of AAV2-hCHM and in uninjected eyes at 2 years of follow-up. Acute (~72 hours) localized foveal thinning and slow, partial recovery of VA in one patient suggests non-vector related individual vulnerability to the subfoveal injection. Residual islands of relatively preserved retina continued to shrink in both injected and uninjected eyes. Longer observation intervals are required to better evaluate the significance of these observations.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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