AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial


Aleman TS, Huckfeldt RM, Serrano LW, Pearson DJ, Vergilio GK, McCague S, Marshall KA, Ashtari M, Doan TM, Weigel-DiFranco CA, Biron BS, Wen X-H, Chung DC, Liu E, Ferenchak K, Morgan JIW, Pierce EA, Eliott D, Bennett J, Comander J, Maguire AM. AAV2-hCHM Subretinal Delivery to the Macula in Choroideremia: Two Year Interim Results of an Ongoing Phase I/II Gene Therapy Trial. Ophthalmology 2022;

Date Published:

2022 Jun 14


PURPOSE: To assess the safety of the subretinal delivery of a recombinant adeno-associated virus serotype 2 (AAV2) vector carrying a human CHM-encoding cDNA in choroideremia (CHM). DESIGN: Prospective, open-label, non-randomized, dose-escalation, phase 1/2 clinical trial. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Fifteen CHM patients (ages 20-57 years at dosing). METHODS, INTERVENTION, OR TESTING: Patients 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=10) AAV2-hCHM. Patients were evaluated pre- and post-operatively for two years with ophthalmic examinations, multimodal retinal imaging and psychophysical testing. MAIN OUTCOME: Measures: visual acuity (VA), perimetry (10-2 protocol), spectral-domain optical coherence tomography (SD-OCT) and short-wavelength fundus autofluorescence (SW-FAF). RESULTS: We detected no vector-related or systemic toxicities. VA returned to within 15 letters of baseline in all but two patients (one developed acute foveal thinning, another patient, a macular hole); the rest showed no gross changes in foveal structure at two years. There were no significant differences between intervention and control eyes in mean light-adapted sensitivity by perimetry, or in the lateral extent of retinal pigment epithelium (RPE) relative preservation by SD-OCT and SW-FAF. Microperimetry showed non-significant (<3SD of the intervisit variability) gains in sensitivity in some locations and participants in the intervention eye. There were no obvious dose-dependent relationships. CONCLUSIONS: VA was within 15 letters of baseline after the subfoveal AAV2-hCHM injections in 13/15 (87%) of the patients. Acute foveal thinning with unchanged perifoveal function in one patient and macular hole in a second suggests foveal vulnerability to the subretinal injections. Longer observation intervals will help establish the significance of the minor differences in sensitivities and rate of disease progression observed between intervention and control eyes.

Last updated on 07/04/2022