Gene Editing Gives Hope for Inherited Blindness

Inherited retinal degenerations are a group of genetic eye diseases that cause progressive vision loss and eventually blindness. Caused by mutations in various genes important for retinal function and survival, these conditions are a leading cause of blindness worldwide, often developing in childhood or young adulthood. One of the most common forms is caused by mutations in the CEP290 gene, which is estimated to account for up to 77% of cases in the United States. Known as CEP290-associated retinal degeneration or Leber congenital amaurosis, this condition leads to severe visual impairment from a very young age. With no approved treatments currently available, affected individuals rely on low vision aids and rehabilitation strategies to maximize their remaining sight.

Now, a small safety study of a promising new gene therapy approach provides early evidence that directly editing the defective gene may restore some vision loss in people with CEP290-associated retinal degeneration. Published in The New England Journal of Medicine, the phase 1/2 clinical trial investigated EDIT-101, a treatment that uses the powerful genome editing system CRISPR-Cas9 to precisely correct the underlying genetic mutation. Delivered via injection beneath the retina, the gene editing complex targeted and removed a specific damaging DNA variation that is present in the majority of cases worldwide. Over the course of a year or more of follow-up, the treatment appeared safe and led to improvements in various measures of vision for many of the trial participants. While the results are preliminary given the small number of individuals involved, they provide proof-of-concept that directly rewriting DNA mutations may offer a new therapeutic strategy for certain inherited retinal diseases.

At the core of CEP290-associated retinal degeneration is a single genetic mutation—a DNA variation known as the c.2991+1655A→G alteration that occurs in the gene’s 26th intron. This intronic mutation results in the production of an abnormal CEP290 protein that disrupts the structure and function of light-sensing photoreceptor cells in the retina. Central to their roles in vision, photoreceptors contain thin projections called sensory cilia that are dependent on proper CEP290 function. The defective protein leads to disorganized outer segments of rods and cones and their premature death, progressively depleting sight. Yet even as vision fails, the underlying retinal neurons and nerve connections into the brain often remain intact. This disconnect between functional impairment and preserved underlying structure provides a therapeutic window of opportunity if interventions can target remaining photoreceptors.

Enter EDIT-101 and its use of the CRISPR-Cas9 gene editing platform. CRISPR stands for “clustered regularly interspaced short palindromic repeats” and describes the bacterial immune system that inspired its adoption for precision DNA changes. Cas9 is an enzyme that cuts or “edits” the genome at specific locations directed by short RNA guide molecules. In EDIT-101, the gene editing payload is delivered into photoreceptors via an injected virus vector with high tropism for the retina. It carries DNA instructions for Cas9 along with two guide RNAs programmed to target the CEP290 mutation site. By permanently removing the intronic variation, the therapy aims to restore normal CEP290 protein production and function.

In the phase 1/2 clinical trial known as BRILLIANCE, researchers administered EDIT-101 via subretinal injection to one eye in 14 participants aged 3 to 63 with the CEP290 mutation. Three ascending dose levels were examined in adults, while children received an intermediate dose. Conducted at five study sites, the open-label study primarily assessed safety over 12-24 months of follow-up while also monitoring various metrics of vision. Happily, no serious side effects were reported from delivery of the gene editing therapy. Most adverse events were mild in severity and involved expected temporary inflammation, which generally resolved within a few weeks. Two adult participants developed subretinal deposits and transient visual impairment around 6 months, but imaging showed retinal structure was otherwise maintained and vision improved with treatment.

On efficacy, improvements were observed across different outcome measures for vision. Promisingly, six participants (43%) experienced clinically meaningful gains in retinal sensitivity to red light as measured by full-field light testing of the treated eye. This suggests enhanced functioning of light-sensing cone photoreceptors targeted by the therapy. For four individuals (29%), visual acuity improved substantially as well. Gains were also seen on mobility tests involving navigating low-light courses and in quality of life questionnaires for vision in six participants (43%). Changes tended to emerge by 3 months and were sustained over time for some. Analysis further revealed the extent of benefit correlated with the degree of pre-existing functional impairment versus retinal structure—those with greater mismatches had larger responses.

Encouragingly, two pediatric cases showed improvements across multiple vision metrics. Studies involving children are particularly significant, as early intervention holds greater potential to influence development and preserve remaining neural connections in the optic pathways. Results from the nine male and five female participants of various ages and ethnicities provide initial evidence the therapy may benefit a genetically and clinically diverse patient population. Viral DNA from the treatment was safely cleared from various tissues within a few months with no detectable immune reactions against the Cas9 protein involved.

While small in sample size, constrained in providing sham comparisons, and with longer follow-up still needed, the study offers an important proof-of-concept that directly rewriting disease-causing DNA mutations is feasible and well-tolerated in humans. It demonstrates restoring normal CEP290 function through in vivo gene editing can enhance retinal photoreceptor performance in those with its deficiency. Outcomes were achieved without detectable safety issues, supporting further development of genetic therapies for retinal degenerations. Future directions will expand enrollment to gain more robust data on efficacy and durability. Combining gene editing with other complementary technologies may further improve outcomes. If verified in larger trials, the approach could ultimately aid not just CEP290 mutations but potentially many other inherited retinal diseases. This work brings hope that gene editing strategies may one day offer a new mainstay for treating blinding conditions rooted deeply in our genome.

Reference(s)

1. DOI: 10.1056/NEJMoa2309915

Click TAGS to see related articles :

CRISP-R | GENETICS | MEDICINE | OPTHALMOLOGY