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Invited Commentary
October 15, 2020

Moving Towards PDE6A Gene Supplementation Therapy

Author Affiliations
  • 1Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston
JAMA Ophthalmol. Published online October 15, 2020. doi:10.1001/jamaophthalmol.2020.4216

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.

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