Abstract
Purpose :
To compare the baseline Pattern ERG (PERG) of Leber hereditary optic neuropathy (LHON) patients with different stages of severe visual loss (≤ 35 ETDRS letters) before gene therapy (GT).
Methods :
The study was part of a phase I GT trial investigating the safety of a scAAV2 investigational product (IP) containing a wild-type synthetic nuclear encoded ND4 subunit for G11778A LHON. Patients (n=28) were enrolled into groups I (GT I: chronic bilateral), II (GT II: acute bilateral), and III (GT III: unilateral, better eye acuity ≥ 70 letters) and tested with PERG prior to IP injection and compared to PERG measurements of 210 normal control (NC) subjects. Steady-state PERGs (SS-PERG) were recorded simultaneously from both eyes and analyzed in the frequency-domain to retrieve amplitude (nV) and phase (deg), which was converted in latency (ms). The SS-PERG latency corresponds to the time-to-peak of the P50 wave of the standard transient PERG. The 2 baseline measurements of each eye were averaged. Then measurements from the 2 eyes of groups GT I, GT II, and NC were averaged yielding 1 measurement per patient. For group GT III, measurements from asymptomatic (GT III-A) and symptomatic (GT III-S) eyes were analyzed separately. Mean amplitudes and latencies were compared with GEE methods followed by post-hoc least significant difference (LSD) tests to account for inclusion of two measurements of GT III patients.
Results :
Ages were similarly distributed in the different subject groups. PERG amplitudes of LHON patients were lower than those of normal controls (p<0.001), but did not differ among patient groups. SS-PERG latencies differed by disease stage (see table) with G III-A shorter than NC (p=0.002) but longer than G III-S (p=0.01). G II (acute bilateral) latencies were further shortened than GIII-S (p=0.03). G I latencies were shorter than NC but did not differ from other GT patient groups (all p>0.1).
Conclusions :
While the baseline SS-PERG amplitude was much reduced in all LHON groups and did not distinguish between disease stage, SS-PERG latency progressively shortened with increasing disease severity. Latency shortening is consistent with LHON pathophysiology whereby smaller/slower axons are primarily affected resulting in the residual response being dominated by larger/faster axons. These results may inform timing of GT injections for preservation of small axons.
This is a 2021 ARVO Annual Meeting abstract.