Therapeutic implications reported in relation to a unique dominant RPE65 mutation with autosomal dominant retinitis pigmentosa (adRP)

Researchers at the Institute of Genetics, TCD, Dublin and the Department of Ophthalmology, McGill University, Montreal have reported significant research results supporting replenishment of the photon capturing compound – oral retinoid – specifically 9-cis retinaldehyde.  While 11-cis retinal is highly unstable (pharmacologically), a synthetic 9-cis retinyl acetate, which is converted in vivo into 9-cis retinal, may now be used stably as a therapeutic intervention and it has been found capable of initiating the visual transduction cycle.  According to the researchers, “phase 1b proof-of-concept study has recently been reported in which aspects of remaining vision were improved for up to one year in four of five patients with advanced disease receiving a single one-week oral dose of 9-cis retinaldehyde, which is the first report showing efficacy and safety of an oral therapy for a dominant form of RP.


Researchers in TCD, and at the University of Texas Health Science Center, had previously identified a mutation, D477G, in the RPE65 gene, showing that the disease was a late-onset form of autosomal dominant RP (adRP) with choroidal involvement.   This was uniquely identified as the only RPE65 variant to be described with a dominant component.  Several other researchers have further characterised RPE65 as a 533 amino acid protein, located on chromosome 1, with 21.5 kilobases comprising 14 exons.   According to the literature, researchers commented that “the number of mutations spread throughout the RPE65 exome has been reported to be 195, half of these being missense (55%), 21% being insertion/deletions, 13% being splicing defects, 9% being nonsense with indels, and a large deletion and a complex rearrangement comprising the remaining 2%”.  It was also shown that review data accrued from published studies of the unique variant was that the clinical spectrum of retinal disease among such patients appear to be highly similar to the pathology of choroideremia.


The D477G variant of RPE65 has reported symptoms of impaired night vision in the 4th or 5th decade, variable nyctalopia and a considerable phenotypic variation, ranging from “normal” vision, to profound visual impairment.  Notwithstanding such, under the phase 1b results, three of five patients, aged 67–68 years, achieved visual field (VF) improvements “of between 70 and 200% of baseline values with maximal responses at 7–10 months”.  Commenting on these preliminary outcomes, one of the authors, Dr. Paul Kenna, stated that, “it is remarkable that after 62 years of retinal disease, it is possible to reactivate dormant photoreceptors with a simple retinoid”.  In addition, this research “may hold promise for younger patients with early stage disease, where periodic retinoid therapy could prove beneficial over prolonged periods of time”. Regardless that the patient numbers were small, there were no serious adverse clinical reactions and therefore it is likely that further larger clinical studies may be initiated to collect larger statistical numbers to support the patient cohorts.