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Despite its early onset, CDH23-associated Usher syndrome type ID progresses slowly, and a wide window for intervention is ideal for novel therapies.

Despite the early onset of symptoms, CDH23-associated Usher syndrome type ID (USH1D) has a slowly progressive phenotype.

Further, the window for intervention may be sufficiently wide, making it an ideal target for novel therapies, according to research published in Investigative Ophthalmology & Visual Science.

There is limited evidence in the literature regarding the retinal phenotype of CDH23-associated USH1D, its natural history, and retinal genotype-phenotype correlations. “This is crucial data to improve counseling of affected patients and families and could also be used as a framework for developing novel treatments in the future,” wrote Thales de Guimaraes, MD, PhD, and colleagues.

The researchers analyzed the natural history, retinal imaging dataset, and clinical features of CDH23-associated USH1D. The retrospective longitudinal study included 31 patients with 40 variants in CDH23 (10 being novel), with a mean age of symptom onset of 10.1 years. The most common visual symptoms were nyctalopia (93.5%) and peripheral vision difficulties (61.3%). The primary outcomes were retinal imaging, electroretinography, and clinical findings, including best-corrected visual acuity (BCVA), outer nuclear layer thickness, ellipsoid zone width, and hyperautofluorescent ring area.

The mean BCVA at baseline was 0.25 ±0.22 in the right eyes and 0.35 ±0.58 logarithmic minimum angle of resolution (LogMAR) in the left eyes. After a mean follow-up of 9.5 years, there was a change in mean BCVA from 0.28 to 0.46 LogMAR, which reached statistical significance (P=0.003). The mean annual loss rate in BCVA was 0.018 LogMAR/year.

The researchers found that 77% of patients had hyperautofluorescent rings in the fundus autofluorescence, with most patients having a ring that remained stable throughout the follow-up period. Full-field and pattern electroretinography indicated moderate-severe rod-cone or photoreceptor dysfunction with relative sparing of macular function in most patients tested. Optical coherence tomography showed intraretinal cysts in the transfoveal B-scan of 13 patients (43.3%). The rate of ellipsoid zone width and outer nuclear layer thickness loss appeared mild, “suggestive of a wide window of macular preservation,” according to Dr. de Guimaraes and colleagues.

While active gene therapies are in progress, the researchers wrote, “The main restriction for gene therapy is the size of the CDH23 gene, which spans about 10.1 kb and is more than twice the cargo capacity of the current generation of adeno-associated viral vectors, the most commonly used vector for gene therapy.”

The authors noted the need for a prospective natural history study to examine disease progression and refine trial endpoints.