1. In this randomized controlled trial, among patients with centrosomal protein 290 (CEP290)-associated retinal degeneration, subretinal injection of EDIT-101 resulted in meaningful improvements in photoreceptor function.

2. EDIT-101 treatment was not associated with serious ocular adverse events.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Hereditary retinal degeneration is caused by many pathogenic gene variants, causing dysfunction and death of photoreceptors and leading to visual impairment. CEP290-associated retinal degeneration involves severe visual impairment and blindness within the first decade of life, with the genetic variant IVS26 being the most common among those in the United States. Patients with this disease, however, maintain intact optic nerves and occipital cortices. EDIT-101 is an adeno-associated virus 5 vector carrying a CRISPR-Cas9 complex to remove the IVS26 variant to restore CEP290 expression. This study was a small phase 1-2 open-label trial to evaluate the safety and efficacy of EDIT-101 for CEP290-associated retinal degeneration. Overall, patients reported improvement from baseline in visual acuity, photoreceptor function, and vision-related quality of life. Moreover, no serious ocular adverse events were reported in study patients. The study was limited by its small sample size, lack of placebo control, and open-label control. Nevertheless, these results demonstrated the potential of EDIT-101 as a safe and efficacious approach to treating CEP290-associated retinal degeneration and prompted further investigation into this modality.

Click here to read the study in NEJM 

In-Depth [randomized controlled trial]: This study was an open-label trial investigating the use of the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas9) EDIT-101 gene therapy in treating CEP290-associated retinal degeneration. Patients at least three years of age at screening who had CEP290-associated inherited retinal degeneration with homozygosity or compound heterozygosity for the IVS26 variant and severe vision loss in the study were eligible for inclusion. Exclusion criteria included prior gene therapy or oligonucleotide exposure, recent vaccination, history of steroid-responsive intraocular pressure, and active systemic or ocular infection or inflammation. Twelve adult patients and two children (aged 9 and 14) underwent unilateral pars plana vitrectomy. They received subretinal injection of EDIT-101 at a low (6×10¹¹ vector genomes [vg]/mL), an intermediate dose (1×10¹² vg/mL), or a high dose (3×10¹² vg/mL). The study’s primary outcome was safety. Secondary efficacy outcomes included change from baseline in best corrected visual acuity, retinal sensitivity to light via full-field stimulus testing (FST), Ora-Visual Navigation Challenge (OVNC) mobility test performance, and quality of life. Patients were monitored for up to two years. A total of 41% of the adverse events were related to the procedure, and 22 ocular adverse events were related to the treatment. Four patients (29%) had improvement in visual acuity, meeting the clinically meaningful threshold. FST testing found six patients (43%) demonstrated a visual meaningful cone-mediated light sensitivity. 4 patients (29%) demonstrated meaningfully improved OVNC scores. Overall, nine patients reported visually meaningful improvements in efficacy outcomes. Lastly, six patients reported improvement in vision-related quality of life from baseline. In summary, this study demonstrated early evidence of the safety of EDIT-101 and its potential efficacy for treating CEP290-associated retinal degeneration.

Image: PD

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