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A longitudinal natural history of USH2A patients, compared with arRP, show valuable outcomes for BCVA, ERG and FST results. 

An international multi-centre study comprised of US, French, German, Dutch and Canadian researchers has reported valuable outcomes for a cohort of USH2A patients.  The natural history showed that USH2A participants had worse BCVA, ERG and FST results, compared to a cohort of patients diagnosed with autosomal recessive retinitis pigmentosa (arRP).  A standardized research protocol initiated a study entitled “Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A)“ in 2017.  The study has monitored disease progression and treatment response looking at prognostic features between USH2 and arRP patients with USH2A mutations.  A brief snapshot of the database shows 20 registered studies listed in Usher’s Syndrome and the current work may provide relevant insights.


Variants in Usher’s syndrome type 2 (USH2A) are well recognised under inherited retinal degenerations (IRDs) and USH2A variants account for 12% to 25% of individuals with non-syndromic arRP, representing the most common cause of arRP.  Children with Usher syndrome type 2 have congenital mild to moderate sensorineural hearing loss (low frequencies) and severe to profound hearing loss (higher frequencies). The RP phenotype may generally manifest during teenage years and has a better visual prognosis than type 1, with almost ~65% patients retaining 6/12 vision in their better eye until 50 years of age.


In the current study, a total of 127 participants were enrolled into the study (NCT03146078), and the top line outcomes showed that USH2 (n=80) had worse BCVA, compared to arRP (n=47) with a median of 79 vs. 82 letters, respectively.  Lower rod-mediated ERG b-wave amplitudes had a median 0.0 for the USH2 cohort compared 6.6 μV for the arRP cohort (p<0.001) and a 30Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 μV; (p=0.001), and higher (white, blue, and red) FST thresholds (means [−26, −31, −23 dB] vs. [−39, −45, −28 dB] (p<0.001 for all stimuli) for USH2 and arRP cohorts, respectively. In summary, the BCVA in USH2 was significantly worse than in patients with arRP, despite a slightly younger median age.  As the full-field ERG was severely reduced among participants, scotopic responses to a dim-flash (DA 0.01) were unmeasurable in 40 (51%) of participants with USH2 compared with 19 (40%) of those with arRP.  Consequently, ERGs were complemented by FST testing, as commented by the researchers who stated that “FST does not require stable fixation and reflects the global light-sensitivity of the remaining photoreceptors. Although it is a less spatially specific measure compared to, for example, microperimetry or static perimetry, it has been used to provide a key reproducible outcome measure for a registration trial of the gene therapy voretigene neparvovec-rzyl (Luxturna) for patients with RPE65-related retinal dystrophy for patients with extremely low vision”. While researchers have presented more FST assays in the literature, it will be interesting to hear comments from regulators in the FDA and EMA to evaluate many clinical end-points.