Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development

The corneoscleral shape in Marfan syndrome

Purpose: To investigate the corneoscleral shape in Marfan syndrome (MFS) patients. Methods: Thirty eyes of 15 participants with molecularly proven MFS were included in this prospective, cross‐sectional study. Optical biometry, Scheimpflug imaging, and corneoscleral topography (Eye Surface Profiler) were performed in all patients. Topographic data were compared to data from controls (25 emmetropes and 17 myopes). The raw three‐dimensional anterior height data from MFS eyes and control eyes were exported for further analysis. Custom‐made software was used to demarcate the limbal radius and to calculate the sagittal height in different concentric annuli centred at the corneal apex, placed in a pupil plane, for the central cornea (0–4 mm radius), peripheral cornea (4–6 mm radius) and sclera (6–8 mm radius) and the corneoscleral asymmetry. Results: Marfan syndrome (MFS) eyes had significantly lower values of mean sagittal height compared to non‐MFS eyes in all three annuli (central cornea, corneal periphery and sclera (independent t‐test, p 0.05). The sclera was significantly more asymmetric in MFS eyes compared to myopes (independent t‐test, p 0.05). Conclusion: The peripheral cornea and sclera of Marfan syndrome patients have a significantly different shape compared to healthy controls