Clinical trial shows CRISPR gene editing has exciting potential to treat a rare form of blindness

  • May 8, 2024
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Clinical trial shows CRISPR gene editing has exciting potential to treat a rare form of blindness

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

Study: Gene Editing for CEP290-Associated Retinal Degeneration. Image Credit: CI Photos/


Inherited retinal degenerations are caused by pathogenic mutations in any of over 280 genes. These mutations cause the photoreceptors (the light-responsive cone and rod cells) of the retina to malfunction and die, resulting in impaired vision in the affected individuals. These conditions are a major cause of blindness globally.

In the condition called CEP290-associated inherited retinal degeneration or Leber’s congenital amaurosis, the centrosomal protein 290 (CEP290) is mutated, leading to partial or complete blindness within the first ten years of life. This is, therefore, the leading cause of genetic retinal blindness in children.

A single gene variant called p.Cys998X accounts for over three-fourths of people with this condition in the USA alone. Normal CEP290 is prevented by the insertion of a single coding segment during transcription. The deficiency of this molecule disrupts normal ciliary action on photoreceptors.

There is no cure at present. Supportive care includes the use of magnifying glasses and Braille with home modifications to promote a safe environment for the visually challenged individual.

At the tissue level, the rods and cones show a loss of organization in the outer retinal segments secondary to the absence of sensory cilia in this condition. The rods in the midperipheral retina die out, while cones remain in the macula, the central point of the retina.

There is a characteristic disconnect between retinal structure and function in these patients. The proximal components of the visual pathway remain intact, indicating that the photoreceptors in these eyes could be used to restore vision. Various approaches that have been explored include the use of antisense oligonucleotides to prevent the expression of the inserted exon (expressed coding segment), or the delivery of the miniaturized version of the CEP290 gene to the cell.

A newer technology makes use of gene editing with the injection of EDIT-101. It is based on the use of clustered regularly interspaced short palindromic repeats (CRISPR) coupled with the CRISPR-associated protein 9 (Cas9) to eliminate the pathogenic IVS26 variant. The current study was meant to examine the safety and efficacy of this therapy.

About the study

The researchers chose to carry out an open-label study in which participants were assigned single doses of the drug in ascending order of dosage. This phase 1-2 study aimed to assess the drug’s safety, while secondary efficacy outcomes were also evaluated.

The safety outcomes included adverse events and unacceptable toxicities that prevented the use of the dosage of interest. Efficacy was measured in various ways, including corrected visual acuity, retinal sensitivity, vision-related quality of life score, and visual navigation mobility testing.

The EDIT-101 gene was injected into 12 adults and two children. The adults ranged from 17 to 63 years old, and the children were nine and fourteen years old, respectively. All had at least one copy of the IV26 variant.

The doses ranged from 6×1011 vector genomes [vg] per mL through 1×1012 vg per mL to 3×1012 vg per mL. Two, five, and five adults received low, intermediate, and high doses, respectively. The children received the intermediate dose.

All injections were into the eye with worse performance, the study eye.

What did the study show?

Most participants had severe loss of visual acuity at below 1.6 logMAR. Visual acuity could be tested only by the Berkeley Rudimentary Vision test as a result. At least 3 log units elevated spectral sensitivity, and rod function was undetectable in all participants.

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

Most adverse events were mild, while about a fifth were moderate, and only about 40% were treatment-related. There were no serious adverse treatment events and no dose-limiting toxicities. The structure of the retina did not show any adverse change, which demonstrated the drug’s acceptable safety.

With respect to its efficacy, this preliminary study showed meaningful improvements in cone vision from baseline levels in six patients. Of these, five also showed at least one other area of improvement.

Improvement in at least one of the following areas (best corrected visual acuity, red light sensitivity, or vision-based mobility) occurred in nine of the patients, that is, almost two out of three in the whole group. Almost 80% had improvements in at least one efficacy-linked outcome and six in two or more outcomes.

Four had an increase of 0.3 logMAR in best-corrected visual acuity, thus meeting the criteria for clinically meaningful improvement. Of these, three reported improvement as early as the third-month post-injection. The mean change in this parameter in the whole group was -0.21 logMAR.

For almost half the group (6/14), the cone sensitivity to light at various frequencies, red, white, and blue, showed a visually meaningful increase in the study eye vs the control eye, some as early as three months later. All had received intermediate to high doses. In two, the improvement reached >1 logMAR, the maximum possible for cones alone.

Cone-mediated sensitivity was greatest in the patients most severely affected at baseline. Almost all patients with improved cone function also showed improvement in one or more other outcomes as well.

Four participants had a visually meaningful improvement in their ability to navigate more complicated courses than at baseline, with one of them continuing to show this improvement for at least two years.

In six participants, clinically meaningful increases were seen in vision-related quality of life scores.

These findings support the presence of productive in vivo gene editing by EDIT-101, therapeutic levels of CEP290 protein expression, and enhanced cone photoreceptor function.”


This small study demonstrated a high safety profile and better visual function in terms of photoreceptor function following the administration of EDIT-101 to participants. These findings “support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes.”

Areas of concern that merit further research include the finding that better cone function following therapy is not synonymous with better visual acuity, which is the clinically meaningful outcome. Secondly, earlier intervention may have better results. Finally, if both copies of the gene are targeted, the therapeutic benefit may be greater.

Journal reference:

  • Pierce, E. A., Aleman, T. S., Jayasundera, K. T., et al. GeneeEditing for CEP290-associated retinal degeneration. The New England Journal of Medicine 2024. doi: 10.1056/NEJMoa2309915.

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