Gene Knock-Out, Replacement Therapy for RP-RHO Performed Well in Lab Study

Editas Medicine reported that EDIT-103, its CRISPR/Cas9 gene-editing and gene-replacement therapy for people with autosomal dominant retinitis pigmentosa (adRP) caused by rhodopsin (RHO) mutations, has performed well in large-animal studies. The company is planning further studies to gain authorization from the US Food & Drug Administration to launch a clinical trial. Results from the large-animal studies were reported by Zoe (Chi-Hsiu) Liu, PhD, a senior scientist from Editas, at the 2022 meeting of the Association for Research in Vision and Ophthalmology (ARVO) held in Denver, May 1–5.

RHO-associated adRP affects about 20,000 people in the US and EU. Approximately 150 mutations in RHO can each cause adRP.

EDIT-103 is designed to “knock-out” copies of the patient’s RHO gene and replace them with healthy copies. The treatment is delivered by a subretinal injection of dual vectors – i.e., dual, adeno-associated viruses (AAVs), which are safe, human-engineered viruses for delivering genetic cargo to retinal cells. One vector contains the CRISPR/Cas9 gene editing technology to turn-off copies of the patient’s RHO gene. The other vector delivers new, healthy copies of RHO.

In a large-animal study, the CRISPR/Cas9 component knocked out 100 percent of the protein expressed by RHO. The healthy, replacement RHO expressed 30 percent of normal protein levels, which Editas believes will be sufficient to treat adRP patients with RHO mutations effectively.

To genetically treat autosomal recessive diseases, simply replacing or augmenting copies of the patient’s mutated gene is usually sufficient, because the mutated copies are expressing little protein. However, in autosomal dominant diseases, a two-step process is often necessary, because the mutated gene copies are expressing a toxic protein. In addition to delivering healthy gene copies, the patient’s mutated copies must be turned off to prevent toxic protein expression.

Editas’ clinical trial for EDIT-101 – a therapy for a mutation in CEP290 causing Leber congenital amaurosis – became the first CRISPR/Cas9 treatment to be applied directly to the human body. In September 2021, Editas reported that two of three patients in the trial had improvements in vision.