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

Abstract

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.

Antisense oligonucleotide therapy for the common Stargardt disease type 1-causing variant in ABCA4

“…AONs have demonstrated promising results in several pre-clinical studies for IRDs, by correcting pathological RNA processing events associated with entire exon skipping, complete degradation of abnormal transcripts or pseudo-exon exclusion. In the clinic, AON-mediated splicing therapy was well tolerated and able to significantly improve the best corrected visual acuity (BCVA) in phase 1 clinical trials with Sepofarsen (LCA10) (Cideciyan et al 2021; Russell et al 2022) and Ultevursen (USH2A associated RP and Usher syndrome) (Dulla et al 2021). These AONs delay disease progression through pseudo-exon and in-frame exon skipping, respectively.…”

“…AON-induced splice modulating activity showed promising therapeutic strategies by exon exclusion, pseudo-exon exclusion and allele-specific degradation of aberrant transcripts for several IRDs, such as autosomal recessive Leber congenital amaurosis, autosomal recessive Usher syndrome type 2A, inherited optic neuropathy and autosomal dominant retinitis pigmentosa (Adamson et al 2017; Bonifert et al 2016; Collin et al 2012; Gerard et al 2012; Murray et al 2015; Slijkerman et al 2016; Dulla et al 2018; Parfitt et al 2016; Russell et al 2022). The ABCA4 protein consists of two transmembrane domains that harbor 6 transmembrane helices each; any truncation within these sites would severely disrupt the complex protein conformation that is required for its correct function (Figure 1A) (Xie et al 2021).…”

Ocular Gene Therapy: A Literature Review With Focus on Current Clinical Trials

“…Currently, the antisense oligonucleotide is under trial for ocular gene therapy for Leber’s Congenital Amaurosis acting on the gene CEP290. This gene encodes for centrosomal protein 290 [ 14 , 15 ].…”

Late-Onset Retinal Degeneration: Clinical Perspectives

“…Trials for clustered regularly interspaced short palindromic repeats (CRISPR) Cas9 gene editing have recently begun aimed at treating other IRD. 32,[61][62][63][64][65][66] The C1QTNF5 mutation in L-ORD is also potentially a target for treatment using CRISPR-Cas9 targeting the mutant alleles. 67 Nonetheless, studies using this type of treatment have also not yet been published.…”