A different type of genetic therapy: correcting a defective gene using antisense oligonucleotide treatment in CEP290 p.Cys998X LCA

Introduction
LCA10, a common form of inherited retinal disease, causes severe childhood-onset vision loss/blindness. Sepofarsen is an RNA therapy targeted to treat LCA10 due to c.2991+1655A>G mutation in the CEP290 gene (p.Cys998X).
Methods
In a 12-month, multicenter, open-label, multiple-dose escalation, phase 1b/2 trial, subjects aged 8–44 years received sepofarsen at loading/maintenance dose of 160/80 μg or 320/160 μg via 1–4 intravitreal injections in the eye with worse best-corrected visual acuity (BCVA). Primary endpoint: frequency and severity of ocular adverse events (AEs) in the treated and untreated contralateral eyes. Secondary endpoints: serum PK, nonocular AEs, and change in functional and anatomic ophthalmic findings.
Results
Eleven subjects were enrolled. Reported cases of cataracts, mild cystoid macular edema, and retinal thinning were 3, 0, and 0, respectively, in the 160 μg / 80 μg group, 5, 2, and 2 in the 320 μg / 160 μg group. No other safety concerns were identified. Pooled data (n = 11) and the 160 μg / 80 μg dose group (n = 6) showed improvements from baseline to month 12 in treated eyes vs untreated eyes in mean ± standard error of the mean (SEM) BCVA (−0.55 ± 0.26 vs −0.12 ± 0.07 logMAR [P < 0.05] and −0.93 ± 0.43 vs −0.22 ± 0.11 logMAR [P = 0.13], resp.), red full-field stimulus test (FST: −0.91 ± 0.18 vs −0.16 ± 0.16 log cd/m2 [P < 0.01] and −0.66 ± 0.14 vs +0.05 ± 0.17 log cd/m2 [P < 0.05]), and blue FST (−0.79 ± 0.23 vs +0.02 ± 0.11 log cd/m2 [P < 0.02] and −0.63 ± 0.31 vs +0.12 ± 0.16 log cd/m2 [P = 0.09]).
Conclusion/relevance
Sepofarsen had a manageable safety profile and showed statistically significant differences for the within-subject improvement in mean BCVA and FST, in adults and children with LCA10. The phase 2/3 trial is ongoing.