An adult with congenital blindness is the first person to receive an in vivo CRISPR-based therapy, according to the sponsors of the clinical trial: Editas Medicine and Allergan. The trial is testing whether EDIT-101 (also known as AGN-151587) can remove a point mutation in the CEP290 gene, which causes type 10 of the retinal degenerative disease Leber congenital amaurosis (LCA). The IVS26 mutation leads to a functional loss in the CEP290 protein, which causes defects in retinal photoreceptors and severe vision loss. To correct the IVS26 mutation, EDIT-101 uses a construct containing the adenovirus vector AAV5 with two guide RNAs to identify the location of the IVS26, combined with DNA encoding the Cas9 enzyme under a promoter specific to photoreceptor cells. Another gene therapy for LCA is Luxturna (voretigene neparvovec-rzyl) from Spark Therapeutics, now owned by Roche. Both Editas and Spark use an AAV vector, but whereas Editas’s genome editing corrects the mutation, Spark’s agent introduces a correct copy of the affected gene. Luxturna is approved for treating specifically the form caused by mutation of the retinal pigment epithelial 65 (RPE65) gene.
In the Editas trial, 18 adult and pediatric participants will receive subretinal injection in a single eye, with any vision improvements anticipated within four weeks of treatment. Also developing a therapeutic for LCA is ProQR Therapeutics. Early results from a phase 1/2 trial of sepofarsen (QR-110), an RNA-based antisense oligonucleotide therapy, showed about 60% of participants improving.
Although EDIT-101 is the first trial using a CRISPR agent inside the body, Sangamo’s zinc finger nuclease therapy SB-913 was the first gene therapy used in vivo, to treat patients with the inherited metabolic disorder mucopolysaccharidosis type II. Until now, clinical trials using CRISPR-based agents had been ex vivo: patients’ cells are removed, edited and then returned to the body. Initial results from a trial of CRISPR Therapeutics and Vertex’s CTX001 in patients with hemoglobin-related blood disorders suggested potentially curative responses in patients with β-thalassemia and sickle cell disease.