After running concurrent trials on the use of unilateral intravitreal (IVT) injections of rAAV2/2- ND4 on patients with Leber’s hereditary optic neuropathy (LHON), a study in Ophthalmology noted that, despite bilateral VA improvement found in eyes treated within six months from onset, the visual outcomes were actually inferior to those seen in eyes treated at later disease stages.

In the RESCUE trial, participants had to have experienced vision loss within six months in at least one eye and for no longer than six months in both eyes so that the researchers could examine treatment outcomes during the subacute phase of LHON. The REVERSE trial was designed concurrently with similar assessment protocols and outcome measures, but these LHON participants had loss of vision in both eyes of six months to a year at study enrollment.

Each participant’s right eye was randomly assigned (1:1) to treatment with injection of rAAV2/2- ND4 (single injection of 9x1010 viral genomes in 90μl) or to sham injection. The RESCUE trial included 38 subjects. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the gene therapy-treated eyes and sham-treated eyes, respectively. The researchers assessed the difference in the change from baseline BCVA between gene therapy-treated and sham-treated eyes at week 48. Follow-up extended to week 96.

For the RESCUE trial, mean baseline logMAR BCVA was 1.31 in gene therapy-treated eyes and 1.26 in sham-treated eyes. At week 48, the difference in the change in BCVA from baseline between gene therapy-treated and sham-treated eyes was -0.01logMAR. The mean BCVA for both groups in the RESCUE trial deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48 and then an improvement of +10 and +9 ETDRS letters equivalent to the plateau level in the gene therapy-treated and sham-treated eyes, respectively. The researchers noted that the RESCUE trial did not meet its primary endpoint of a -0.3logMAR (15-letter) difference.

The study found a greater baseline RNFL thickness among RESCUE patients compared with REVERSE patients (mean RNFL thickness 99.1μm vs. 69.7μm, respectively) that likely reflects a combination of less nerve fiber loss and more axonal swelling in the earlier stages of LHON. “It is possible that RNFL thickness may play a role by imposing a physical barrier to the diffusion of the treatment to retinal ganglion cells and potentially impeding the distribution of the viral vector throughout the RNFL after viral transduction,” the researchers speculated.

Newman NJ, Yu-Wai-Man P, Carelli V, et al. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within six months of disease onset. Ophthalmology. January 12, 2021. [Epub ahead of print].