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

Retinal degeneration can be hereditary or acquired. In the first 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 cones and rods) in the retina to malfunction and die, resulting in 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 to complete blindness within the first ten years of life. It is therefore the leading cause of genetic blindness in children caused by retinal damage.

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

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

At the tissue level, rods and cones become disorganized in the outer segments of the retina due to the lack of sensory cilia in this condition. The rods in the mid-peripheral retina die off, while the cones are preserved in the macula, the central point of the retina.

A characteristic feature in these patients is a disconnect between retinal structure and function. The proximal components of the visual pathway remain intact, suggesting that the photoreceptors in these eyes may be used to restore vision. Various approaches being studied include using oligonucleotides to prevent the 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 an injection called 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 efficacy of this therapy.

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

The safety endpoints studied included adverse events and unacceptable toxicity that prevented the use of the dose of interest. Performance 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 introduced into twelve adults and two children. The adults ranged in age from 17 to 63, and the children were nine and fourteen years old, respectively. All had at least one copy of the IV26 variant.

Doses ranged from 6x10^11 vector genomes per ml to 3x10^12 vector genomes per ml. Two, five and five adults received low, medium and high doses, respectively. Children received an average dose.

All injections were given in the worst performing eye, 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 rudimentary vision test. There was at least a 3 log increase in spectral sensitivity 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 treatment-related serious adverse events and no dose-limiting toxicities. The structure of the retina did not show any undesirable changes, which demonstrates the acceptable safety of the drug.

In terms of 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 areas (best corrected visual acuity, red light sensitivity, or vision-based mobility) was observed in nine patients, 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 clinically significant improvement. Of these, three reported improvement just three months after the injection. The average change in this parameter in 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 visually significant increases in the test eye compared to the control eye, some as early as three months. All received medium and high doses. In two, the improvement reached >1 logMAR, the maximum possible only for cones.

Cone-induced sensitivity was greatest in patients most severely affected at baseline. Almost all patients with improved conus 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 administering EDIT-101 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 relevant measure. Second, earlier intervention may produce better results. Finally, if both copies of the gene are targeted, the therapeutic benefit may be greater.