Therapeutic Window for Phosphodiesterase 6–Related Retinitis Pigmentosa

In this issue of JAMA Ophthalmology, Khateb et al¹ fill a key knowledge gap by providing a comprehensive retrospective analysis of retinitis pigmentosa (RP) disease progression over time in a large cohort of 54 patients with either PDE6A or PDE6B mutations. Their findings revealed 29 novel PDE6A and PDE6B variants among 49 that were identified. Using a wide range of variables as outcome measures—including multimodal retinal imaging, best-corrected visual acuity, full-field electroretinography, and kinetic visual fields—in some cases with more than 15 years of follow-up, Khateb et al¹ found similar rates of disease progression between both genetic groups, although nyctalopia was a more prevalent symptom in patients with PDE6A.

Phosphodiesterase-6 (PDE6) is one of the most studied phototransduction enzymes with an overwhelming amount of promising translational and clinical data.^2–5 The PDE6 genes encode a key phototransduction enzyme, rod-specific cyclic guanosine monophosphate (cGMP) phosphodiesterase 6, composed of 1 α (PDE6A; OMIM 180071), 1 β^6,7 (PDE6B; OMIM 180072), and 2 inhibitory γ (PDE6G; OMIM 180073) subunits. Upon light-induced activation, the γ subunits of PDE6 are displaced via G-protein activity, causing a surge in cGMP hydrolysis and subsequent cGMP-mediated rod hyperpolarization. As such, autosomal-recessive mutations in PDE6A, PDE6B, or PDE6G lead to a rise in calcium and sodium ions that triggers photoreceptor cell death.

A wealth of evidence stemming from preclinical PDE6 RP animal models suggests that PDE6-related RP is a directly treatable disease with a wide therapeutic time window. Mowat et al² accomplished effective gene augmentation therapy in Pde6a-mutant Cardigan Welsh corgi dogs through subretinal injection of capsid-mutant AAV-Pde6a—a milestone instance of vision-restoring gene therapy performed in a large animal. Other studies using Pde6 mouse models—the most commonly studied RP animal model worldwide—have elucidated avenues for metabolomics- and gene-based therapy. By reprogramming rod photoreceptors into perpetual glycolysis in Pde6b^H620Q/Pde6b^H620Q mice, Zhang et al⁴ revealed a novel, non–gene-specific metabolome reprogramming for enhancing photoreceptor survival in RP. Even advanced stages of RP were proven to be treatable in Pde6b^H620Q/Pde6b^H620Q mice, suggesting that RP possesses a fairly large therapeutic time window after which the disease is considered too advanced for therapy.⁵

The contribution of Khateb et al¹ is timely in the context of emerging human gene therapy clinical trials. PDE6, although rare in the absolute sense, is the most common cause of autosomal-recessive RP following USH2A and EYS; PDE6A was found to occur in approximately 2 of 173 cases of autosomal-recessive RP, and PDE6B was found to occur in 4 of 92 cases.⁸ It is therefore no surprise that the work of Khateb et al¹ is among a growing number of translational and clinical PDE6 research studies available to date. Their article is impressive in that it summarizes one of the largest longitudinal cohorts of patients with PDE6A and PDE6B mutations who have RP studied thus far.

Unique to their study is the use of kinetic visual fields as a functional outcome measure of RP progression. The subgroup of patients that underwent Goldmann kinetic visual field testing exhibited sizable degrees of vision (a mean of 13°–14° in both genetic groups) that allowed for a detectable decrease in visual field over time. This finding suggests that the disease progression in a substantial number of patients with PDE6 mutations may be monitored using kinetic visual field testing as an outcome measure in interventional clinical trials. Khateb et al¹ also quantitatively characterized the rate of decrease of the horizontal and vertical diameters of the hyperautofluorescent ring in RP over time. An analysis of these rates of ring constriction suggested that, as RP progresses, the shape of the ring gradually evolves from an ellipse to a circle—a novel finding that could serve as a prognostic aid or a marker of disease progression in clinical settings and trials. These and other findings in the work of Khateb et al¹ will have considerable implications on the design, duration, and outcome measurements of future PDE6-related RP clinical trials yet to come.