Abstract
Purpose :
To rescue visual loss in a mouse model of LHON, a blinding mitochondrial disease primarily affecting retinal ganglion cells (RGC) and their axons using a mitochondrial-targeted AAV2(MTS-AAV) carrying a wildtype human ND4 gene.
Methods :
DBA/1J mice (N=40) were injected intravitreally (IVI) with MTS-AAV carrying mutant human ND4 (hND4G11778A, 6 E9 vg/eye) and two days later randomly divided into LHON and LHON rescue groups. The LHON group (N=20) received MTS-AAV delivered mitochondrial-encoded cherry (mCherry, 6E9 vg/eye), and the rescue group (N=20) received MTS-AAV delivered wildtype hND4 under the control of the mitochondrial heavy strand promoter including 3 upstream conserved sequence blocks ( HSPCSB-hND4, 6 E9 vg/eye). A control group (N=20) received two IVI of MTS-AAV delivered mCherry(6 E9 vg/eye). The three groups were longitudinally monitored over 12 months with pattern ERG (RGC function), IOP, and OCT. Retinal visual acuity were measured by PERG at 12-month-old. At endpoint, optic nerves and retinas were harvested for RGC (RBPMS) and axon (TEM) density. Longitudinal data were analyzed using generalized estimating equation (GEE).
Results :
Figure 1 shows that PERG amplitudes declined with increasing ages in all three groups (P< 0.001), however, with significant differences (P = 0.023) among groups (Control > LHON, P = 0.008; Control vs. LHON-rescue, P = 0.228. OCT-determined inner retina thickness and IOP did not change significantly with ages and groups. Retinal visual acuity was improved in rescue group (0.305 ± 0.1 cyc/deg, N=3) compared with LHON mice (0.108 ± 0.101 cyc/deg, N=3). RGC and axon counts are in progress.
Conclusions :
A high-tilter mitochondrially targeted vector (MTS-AAV2) carrying the wild-type human ND4 gene is able to rescue, at least in part, visual loss in a mouse model of LHON.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.