In this issue of JAMA Ophthalmology, Kuehlewein and colleagues1 present genetic and clinical findings for an autosomal recessive form of an inherited retinal degeneration (IRD) associated with sequence variations in PDE6A (OMIM, 180071), the gene encoding the α subunit of the rod photoreceptor cyclic guanosine monophosphate (cGMP) phosphodiesterase.2 The authors1 have gathered what appears to be the largest cohort to date, 57 patients, who were followed up over a period of approximately 3 years with their course of disease evaluated in preparation for a gene supplementation trial. Overall, the researchers concluded that retinal pigmentosa associated with biallelic sequence variations in PDE6A showed a mild to moderate disease (mean [SD] age at baseline, 40[14] years), and the disease course was predictable and highly symmetrical between the eyes. Despite the relatively mild disease, most patients had small visual fields by their 30s, and a few patients retained detectable rod function by ERG. This suggests that relatively young patients would be the best candidates for gene therapy requiring viable rods. Currently, there are 3 registered natural history studies of patients with PDE6A sequence variations (NCT02759952, NCT04285398, and NCT03975543), indicating interest in gene therapy for this gene. This is not to mention that these types of studies help clinicians in making more accurate prognoses for patients who need prognostic information.
The PDE6A gene was associated with autosomal recessive rod-cone dystrophy (or retinitis pigmentosa) in the mid-1990s, and since then, its biology has been well established.2 The PDE6A subunit is 1 of the 4 rod photoreceptor cGMP phosphodiesterase (PDE6) subunits, which also includes the catalytic β subunit, PDE6B (OMIM, 180072) and 2 inhibitory γ subunits, PDE6G (OMIM, 180073), both of which are associated with retinal disease.3,4 Phosphodiesterase is essential for rod phototransduction. Conformational change of a rhodopsin molecule after absorption of a photon activates PDE6, which in turn hydrolyzes cGMP, leading to a closure of cyclic nucleotide-gated channels, cell hyperpolarization, and transmission of an electrochemical signal to second-order neurons.5 Sequence variations in any of the PDE6 components thus not only block the phototransduction signal transmission but also lead to elevated levels of cGMP, which are toxic to the cell.5
Development of successful therapies requires a good understanding of the pathophysiology of the disease and availability of adequate animal models that recapitulate the disease. There are several animal models of PDE6A retinal disease: 3 mouse lines carrying missense sequences variations and a Cardigan Welsh Corgi dog breed with a spontaneous frame-shifting sequence variation. Gene supplementation therapy in mice and dogs has shown promising results with effective photoreceptor cell rescue, especially when applied early in the degeneration, when a substantial number of rods is still available.6–9 Two of the studies7,9 used a vector developed for the use in human patients, showing cross-species efficacy and demonstrating that use of a canine model in a preclinical safety and efficacy trials is possible.
Based on the patients’ natural history of disease and animal studies, Kuehlewein and colleagues1 recognized the importance of identifying patients as early as possible in their disease to maximize the number of remaining viable and treatable rods. With the increasing availability and continuously decreasing prices of DNA sequencing, one would assume that identifying all of the patients who can benefit from the PDE6A gene supplementation therapy is an easy task. Unfortunately, this is not as simple as it sounds, partly because of a large genetic heterogeneity of IRDs, with more than 270 genetic forms of disease.10 Sequence analysis of all of the IRD genes often renders unclear solutions: variants that cannot be easily interpreted as pathogenic, likely causal variants in multiple IRD genes, or no likely genetic solutions at all.
Another complication is that for identifying disease causing sequence variations in recessive genes, such as PDE6A, it is imperative that both variants are inherited in trans, that is, 1 on a maternal allele and 1 on the paternal allele. These issues were recognized by Kuehlewin and colleagues1 in their own cohort, in which 9 of 57 individuals had causal variants that could not be indisputably identified and/or for which familial segregation of the variants was not available. It is possible that uncertain genetics would preclude some of these individuals from gene therapy, which is very unfortunate. This invites a reflection on the current capabilities of genetics, in which, despite all recent technological advances and worldwide collaborative efforts, we still do not know or cannot be certain of the genetic source of disease in about one-third of the patients with IRD. To be able to keep up with the emerging gene therapies and identify all eligible patients, additional work is necessary to uncover elusive genetic causality of IRDs and facilitate the interpretation of variants of unknown significance. High-throughput functional genomics and modeling of coding and noncoding variants will be increasingly important, as well as long-read DNA sequencing to detect structural changes and phase compound heterozygous variants.
Application of these new approaches is timely and needed, especially for patients who may benefit from the ongoing progress in gene therapy. Stepping back, it is impressive that we have come to a point where the field is building on Luxturna, the first US Food and Drug Administration-approved gene therapy for any inherited disease, and is now steadily working toward understanding and treating multiple forms of inherited retinal diseases.
Acknowledgments
Conflict of Interest Disclosures:
Dr Bujakowska reports support from the National Eye Institute (grant R01EY026904), the Foundation Fighting Blindness (grant EGI-GE-1218-0753-UCSD), and the Research to Prevent Blindness International Research Collaborators Award. Dr Comander is supported by the National Eye Institute (grant R01EY031036) and Foundation Fighting Blindness and a paid consultant for AGTC, Biogen, Gensight, Sanofi, Vedere, and Wave Therapeutics.
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