CRISPR gene editing holds great promise for treating a rare form of blindness

Retinal degeneration can be inherited or acquired. In the former case, it is an incurable and progressive disease. A recent study published in the New England Journal of Medicine explored the potential use of gene editing to correct a congenital retinal degeneration called CEP290, which causes early vision loss.

Inherited retinal degenerations are caused by pathogenic mutations in any one of more than 280 genes. These mutations cause the photoreceptors (light-sensitive rods and cones) in the retina to malfunction and die, leading to vision loss in affected individuals. These conditions are a leading cause of blindness worldwide.

In CEP290-associated retinal degeneration or Leber's amaurosis, the mutated centrosome protein 290 (CEP290) causes partial or complete blindness within the first ten years of life. It is therefore the leading cause of genetic blindness in children caused by retinal damage.

One genetic variant, called p.Cys998X, accounts for more than three-quarters of cases of the condition in the U.S. alone. The normal functioning of CEP290 is blocked by the insertion of a single coding segment during transcription. Deficiency of this molecule disrupts normal ciliary action on photoreceptors.

There is currently no cure. Supportive care includes the use of magnifying glasses and Braille, as well as home modifications to create a safe environment for people with visual impairments.

At the tissue level, rods and cones become disorganized in the outer segments of the retina due to the absence of sensory cilia in this state. Rods in the mid-peripheral retina die off, while cones persist in the macula, the central point of the retina.

A characteristic feature of these patients is a disconnect between retinal structure and function. Proximal components of the visual pathway remain intact, suggesting that the photoreceptors in these eyes may be used to restore vision. Various approaches being explored include using oligonucleotides to prevent expression of the inserted exon or delivering a miniature version of the CEP290 gene into the cell.

The latest technology involves the use of gene editing with the injection of EDIT-101. It is based on the use of the clustered regularly interspaced short palindromic repeats (CRISPR) system in combination with the CRISPR-associated protein 9 (Cas9) protein to eliminate the pathogenic variant IVS26. This study aimed to study the safety and effectiveness of this therapy.

The researchers decided to conduct an open-label study in which participants were given single doses of the drug in ascending order. This Phase 1-2 study aimed to assess the safety of the drug, while secondary efficacy outcomes were also assessed.

Safety endpoints included adverse events and unacceptable toxicity that prevented use of the dose of interest. Efficacy was measured in a variety of ways, including corrected visual acuity, retinal sensitivity, vision-related quality of life assessment, and vision navigation mobility testing.

The EDIT-101 gene was injected into twelve adults and two children. The adults ranged in age from 17 to 63, while the children were nine and fourteen years old, respectively. All had at least one copy of the IV26 variant.

Doses ranged from 6×10^11 vector genomes/mL to 3×10^12 vector genomes/mL. Two, five, and five adults received low, medium, and high doses, respectively. Children received the medium dose.

All injections were given into the eye with the worst performance, the study eye.

What did the study show? Most participants had severe visual acuity loss below 1.6 logMAR. Visual acuity could only be tested using the Berkeley Vestigial Vision Test. Spectral sensitivity increased by at least 3 log units, and rod function was undetectable in all participants.

However, photoreceptor layer thickness was within normal limits in most patients, as expected.

Most side effects were mild, about a fifth were moderate, and only about 40% were treatment-related. There were no serious treatment-related adverse events and no dose-limiting toxicities. Retinal structure showed no adverse changes, demonstrating acceptable safety of the drug.

As for its effectiveness, a preliminary study showed significant improvements in cone vision from baseline levels in six patients. Of these, five showed improvement in at least one other area.

Improvement in at least one of the following domains (best-corrected visual acuity, red-light sensitivity, or vision-based mobility) was seen in nine patients, or nearly two out of three in the entire group. Nearly 80% had improvements in at least one performance measure, and six had improvements in two or more measures.

Four showed a 0.3 logMAR increase in best corrected visual acuity, thus meeting the criteria for a clinically significant improvement. Of these, three reported improvement as early as three months after injection. The mean change in this parameter for the entire group was -0.21 logMAR.

For nearly half the group (6/14), cone sensitivity to light at different frequencies, red, white and blue, showed a visually significant increase in the study eye compared to the control eye, some after only three months. All received medium and high doses. Two showed an improvement of >1 logMAR, the maximum possible for cones alone.

Cone-mediated sensitivity was greatest in patients most severely impaired at baseline. Almost all patients with improved cone function also showed improvement in one or more other measures.

Four participants showed visually significant improvement in their ability to navigate more complex trails compared to baseline, one of whom continued to show this improvement for at least two years.

Six participants experienced clinically significant increases in vision-related quality of life scores.

"These results confirm the presence of productive in vivo gene editing by EDIT-101, therapeutic levels of CEP290 protein expression, and improved cone photoreceptor function."

This small study demonstrated a high safety profile and improved photoreceptor function after EDIT-101 was administered to participants. These results “support further in vivo studies of CRISPR-Cas9 gene editing for the treatment of inherited retinal degenerations caused by the IVS26 CEP290 variant and other genetic causes.”

Areas worthy of further investigation include the finding that improved cone function after therapy does not equate to improved visual acuity, which is a clinically meaningful measure. Second, earlier intervention may yield better results. Finally, targeting both copies of the gene may result in greater therapeutic benefit.