CRISPR: A promising path to treating blindness (2024)

Research in CRISPR/Cas9 technology finally came to fruition when Casgevy was approved by U.S. and European regulators to treat two blood disorders – sickle cell disease and beta-thalassemia. Rigorous research in the CRISPR field, which has been going on for more than a decade now, might just pay off, as scientists believe that it could treat a range of genetic diseases including blindness.

CRISPR trial sees success in patients with a rare form of blindness

Researchers at Oregon Health & Science University conducted a clinical trial for patients with a rare form of blindness called inherited retinal degeneration (IRD). Visual impairment in IRD occurs when the structure and function of the retina – a layer that converts light into electrical signals – is altered often due to genetic mutations.

The gene editing candidate, EDIT-101, developed by Massachusetts-based Editas Medicine, has been designed to correct the mutation in the CEP290 gene, which codes for a protein that is linked to sight. This mutation causes Leber congenital amaurosis, a rare genetic eye disorder that causes blindness at birth, for which there is no cure.

79% of the 14 patients – 12 adults and two children – showed improvement with treatment. This ‘improvement’ was based on four factors including visual acuity, which is the ability of the eye to distinguish shapes of objects at various distances. Others were how well participants saw colored points of light, how well they navigated a research maze with obstacles and regions with varying amounts of light, and finally, how the treatment affected their quality of life.

In 79% of these patients, at least one of these boxes was checked, and in around 43%, at least two. 43% of the patients also reported that their quality of life had gotten better, and 29% were able to identify objects and alphabets on a chart. The trial saw mild side effects, all of which were resolved.

“This research demonstrates that CRISPR gene therapy for inherited vision loss is worth continued pursuit in research and clinical trials,” said Eric Pierce, ophthalmologist at Mass Eye & Ear in Boston, who was a corresponding author on the study, in a press release. “While more research is needed to determine who may benefit most, we consider the early results promising. To hear from several participants how thrilled they were that they could finally see the food on their plates – that is a big deal. These were individuals who could not read any lines on an eye chart and who had no treatment options, which is the unfortunate reality for most people with inherited retinal disorders.”

How does CRISPR treat blindness?

CRISPR is a cut-and-paste tool and is short for clustered regularly interspaced short palindromic repeats. Jovi Boparai, founder and chief executive officer (CEO) at U.S.-based CorneaCare, explained that using CRISPR to target mutated retinal cells involves three major steps. The first being identifying the specific DNA mutation, followed by creating the delivery system – which, in the case of EDIT-101 is an adeno-associated virus (AAV) vector – to carry the CRISPR machinery, and then, releasing the CRISPR payload into the retinal cells in the eye.

The gene editing machinery has a guide RNA and the Cas9 enzyme, which is used to cut DNA at the site of the mutation.

“The guide RNA serves as a GPS for the cleaving enzyme to target the mutated DNA. After the mutated DNA is cleaved, the body’s DNA repair mechanisms kick in to rejoin the DNA without the mutation, but this process can lead to unintended DNA variants,” said Boparai. “Alternatively, the CRISPR machinery may carry a healthy copy of the DNA, which can be inserted in place of the mutated DNA. However, this requires that the healthy DNA is known and that it can be included in the CRISPR payload.”

The reason why CRISPR is used instead of simply delivering a working copy of the mutated gene – like with FDA-approved Hemgenix that delivers the factor IX gene to treat hemophilia B – is because the CEP290 gene is too big to fit into an AAV vector.

While further trials could confirm CRISPR’s success in treating genetic eye disorders, it cannot restore sight loss in all forms of blindness as many do not have a specific DNA mutation associated with it. Boparai pointed out that CRISPR holds the most potential in treating diseases that have a specific, targetable DNA mutation, such as Leber congenital amaurosis, retinitis pigmentosa – a genetic eye disease characterized by black pigmentation – and certain retinal dystrophies.

Challenges of CRISPR technology

However, the technology is not without its limitations. The ability of these molecular scissors to perform is predicated on the knowledge of the specific gene mutations that drive the disease.

“Mapping out the disease genome for conditions causing blindness is critical to figuring out which pathologies can be targeted,” said Boparai.

Moreover, the accuracy of the delivery as well as its effectiveness has been questioned.

“There are multiple different cell types in the human retina, and to precisely deliver the CRISPR machinery to the cells with the mutated DNA is technically difficult. If the CRISPR machinery ends up in normal cells, it may cause unintended consequences,” said Boparai.

If the scissors cut at the wrong site, unforeseen genetic alterations may occur, and so, mitigating these risks is a priority. Even if the CRISPR machinery reaches the correct target cells, Boparai explained that there is some concern that the cleaving enzyme may accidentally target normal DNA and delete chunks of it, which would likely lead to the disruption of other genes.

“Beyond the above scientific challenges, there are ethical and regulatory concerns. As CRISPR technology becomes more precise, it’ll be crucial to discuss the ramifications of this on all humans. Guidelines will be required from regulatory bodies to ensure the safe and effective use of CRISPR,” said Boparai.

Editas’ previous attempt at treating vision loss with CRISPR

Keeping in mind these issues, how patients have responded to EDIT-101 is crucial to realizing the safety and efficacy of the therapy. But this recent trial is not the first time the candidate was offered up to target blindness.

The first time EDIT-101 entered the clinic, which was also the world’s first attempt to use the CRISPR gene-editing tool to treat blindness, was back in 2020. However, the five-patient trial was not entirely triumphant in eliciting a response in all of the patients. Three patients did not see a change but two patients were able to sense more light after being treated with EDIT-101.

In fact, one of the patients’ visual acuity tests improved significantly after the therapy. She went from not being able to read certain alphabets on the test chart to recognizing them. The other patient whose condition got better, regained more peripheral vision.

While the recent results seem to corroborate the positive results from the 2020 study, it has also one-upped the previous trial results as more patients were involved, and more robust responses were observed. Currently, the researchers at the different trial sites across the U.S. including Oregon Health & Science University and Mass Eye and Ear, along with the trial sponsor Editas, are looking for another partner to continue research, and bring the therapy ahead in clinical trials.