Releasing the Gene Genie

The last four months have seen a number of landmarks in retinal gene therapy for retinitis pigmentosa (RP). In April, Robert MacLaren performed the first ever human subretinal injection of AAV-XLRPGR gene therapy. But last month, the first phase III clinical trial data were published of Spark Therapeutics’ voretigene neparvovec (AAV2-hRPE65v2), as a potential one-time gene therapy candidate for the treatment of patients with vision loss (20/60 or worse) due to confirmed biallelic RPE65-mediated inherited retinal disease (1). In one week in November 2013, 31 individuals were enrolled with 21 being randomized to receive bilateral subretinal voretigene neparvovec injections, and 10 to receive control injections – although one patient from each group withdrew before the injections occurred.

Just like with retinal prostheses, one of the big questions that has to be answered when people perform clinical trials of gene therapies for retinal degenerative diseases like RP is: how do you measure improvement in (or deterioration of) visual outcomes? The Snellen chart isn’t particularly informative here. Instead, the investigators chose the change in multi-luminance mobility testing (MLMT) as the trial’s primary endpoint. MLMT is a visual assessment that integrates aspects of visual acuity testing, visual field testing and light sensitivity into a quantifiable measure (2). How? With an assault course – or rather, trial participants were instructed to follow arrows on the MLMT course, while avoiding obstacles in or adjacent to the path, traversing raised steps, and identifying a door at the end of the course. Several light levels (ranging from 1–400 lux) were evaluated in order to determine the lowest light level at which participants could successfully navigate the course.

So how did the participants fare? After one year, mean bilateral MLMT score changes were 1.8 (SD 1.1) in the intervention group, and 0.2 (SD 1.0) in the control group (a 1.6 unit difference, 95% CI 0.72–2.41, p=0.0013). As a practical measure, 13 of the 20 participants who received the gene therapy managed to complete the MLMT course at the lowest luminance level tested (1 lux), whereas not one of the control group managed to achieve this. Significant improvements, relative to control, were seen in full-field light sensitivity threshold testing (p=0.0004), and visual field area with Goldmann III4a stimulus testing (p=0.0059) too, although the change in visual acuity averaged over both eyes was not (p=0.17). Hearteningly, no therapy-related serious adverse events were observed, and perhaps thanks to the perioperative immunomodulatory regimen employed, “no deleterious immune responses occurred.”

The study authors succinctly (and modestly) summarized their work with, “Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable.” The era of gene therapy for retinal disease outside of the clinical trial setting looks like it’s got a whole lot closer.