Retinal degeneration can be hereditary or acquired. In the first 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 vision loss.
Study: Gene editing for CEP290-Associated Retinal Degeneration. Image credit: CI Photos/Shutterstock.com
Record
Hereditary retinal degenerations are caused by pathogenic mutations in any of 280 genes. These mutations cause the photoreceptors (the cone and rod cells that respond to light) of the retina to malfunction and die, resulting in impaired vision in affected individuals. These conditions are a leading cause of blindness worldwide.
In the condition called CEP290-related hereditary retinal degeneration, or Leber congenital macular degeneration, 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 more than three-quarters of people with the condition in the US alone. Normal CEP290 is prevented by the insertion of a single coding segment during transcription. Deficiency of this molecule disrupts normal ciliary action in photoreceptors.
There is currently no cure. Supportive care includes the use of magnifying glasses and Braille with home modifications to promote a safe environment for the visually impaired person.
At the tissue level, rods and cones show a loss of organization in the outer retinal segments secondary to the absence of sensory cilia in this condition. Rods in the mesoperipheral retina die, while cones remain in the macula, the center of the retina.
There is a characteristic disconnection between retinal structure and function in these patients. Proximal elements 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 using antisense oligonucleotides to prevent expression of the inserted exon (expressed coding segment) or delivering the micro-version of the CEP290 gene into the cell.
A newer technology makes use of gene editing by injecting EDIT-101. It is based on the use of clustered regularly interspaced short palindromic repeats (CRISPR) in combination with CRISPR-associated protein 9 (Cas9) to eliminate the pathogenic variant IVS26. The current study aimed to examine the safety and efficacy of this treatment.
About the study
The researchers chose to conduct an open-label study in which participants received individual doses of the drug in ascending order of dosage. This phase 1-2 study aimed to assess the safety of the drug, while secondary efficacy outcomes were also assessed.
Safety outcomes included adverse events and unacceptable toxicities that precluded use of the dose of interest. Efficacy was measured in several ways, including corrected visual acuity, retinal sensitivity, vision-related quality of life score, and visual navigation motor test.
The EDIT-101 gene was injected into 12 adults and two children. The adults ranged in age from 17 to 63, and the children were nine and fourteen, respectively. All had at least one copy of the IV26 variant.
Doses ranged from 6×1011 vector genomes [vg] per mL to 1×1012 vg per mL at 3×1012 vg per mL. Two, five, and five adults received low, intermediate, and high doses, respectively. Children received the intermediate dose.
All injections were made in the worse performing eye, the study eye.
What did the study show?
Most participants had severe visual acuity loss below 1.6 logMAR. As a result, visual acuity could only be tested with the Berkeley Rudimentary Vision test. At least 3 units of recording increased 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 side effects were mild, with about one-fifth moderate and only about 40% treatment-related. There were no serious adverse treatment effects and no dose-limiting toxicities. The structure of the retina did not show any adverse changes, which proved the acceptable safety of the drug.
In terms of its effectiveness, this preliminary study showed significant improvements in cone vision from baseline 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) was noted in nine of the patients, or almost two out of three in the entire group. Almost 80% had improvements in at least one efficacy-related outcome and six in two or more outcomes.
Four had a 0.3 logMAR increase in best-corrected visual acuity, thus meeting criteria for a clinically significant improvement. Of these, three reported improvement as early as the third month after the injection. The mean change in this parameter in the whole group was -0.21 logMAR.
For almost half the group (6/14), cone sensitivity to light at various frequencies, red, white and blue, showed a visually significant increase in the study eye over the control eye, some as early as three months later. All had received intermediate to high doses. In two, improvement reached >1 logMAR, the maximum possible for cones only.
Cone-induced sensitivity was greater in patients more severely affected at baseline. Almost all patients with improved cone function also showed improvement in one or more other outcomes.
Four participants had a visually significant improvement in their ability to navigate more complex lessons than at baseline, with one of them continuing to show this improvement for at least two years.
In six participants, clinically significant increases in vision-related quality of life scores were observed.
“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.”
conclusions
This small study showed a high safety profile and better visual function in terms of photoreceptor function after EDIT-101 was administered 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 warrant further investigation include the finding that better cone function after treatment is not synonymous with better visual acuity, which is the clinically relevant outcome. Second, earlier intervention may have better results. Finally, if both copies of the gene are targeted, the therapeutic benefit may be greater.
