How can gene therapies address inherited blindness?

Luxturna

The only FDA-approved treatment for inherited blindness is Luxturna (voretigene neparvovec-rzyl), which SPARK Therapeutics developed. Luxturna is a gene therapy approved in December 2017 for patients with inherited blindness. According to the FDA approval announcement, it was “the first directly administered gene therapy approved in the United States that targets a disease caused by mutations in a specific gene.”

The drug is indicated for patients with biallelic mutations in their RPE65 gene, associated with retinal dystrophy and vision loss. The FDA notes that biallelic RPE65 mutation-associated retinal dystrophy impacts roughly 2,000 patients in the US. The condition involves mutations in the maternal and paternal RPE65 gene, which is supposed to code for enzyme production that facilitates normal vision.

Through a subretinal injection, Luxterna works to restore vision loss by delivering an undamaged copy of the RPE65 gene using adeno-associated viral (AAV). This treatment is a one-time procedure in each eye performed approximately six days apart for a total of two procedures that restore vision in patients with viable retinal cells.

According to , multiple clinical trials support the use of this medication. Researchers assessed the drug's efficacy by having patients complete the multi-luminance mobility test (MLMT) — an obstacle course done at varying light levels — and comparing pre- and post-treatment performance. One year after treatment, patients given Luxturna could see and navigate MLMT at two light levels darker than before treatment. GoodRx Health notes that roughly 65% of patients given the treatment could complete the MLMT at the lowest light level.

Despite the benefits and efficacy of the drug, Luxturna can cause eye redness, swelling, pain, deposits underneath the retina, corneal thinning, high ocular pressure, cataracts, macular holes or wrinkling, and retinal tears. Other side effects, such as eye infections, retinal changes, and permanent vision loss, may be caused by the procedure. 

 The drug costs $425,000 per eye for $850,000 per patient.

CRISPR-Based Gene Editing for Blindness

Although there is only one FDA-approved gene therapy for inherited blindness, many ongoing studies and research projects focus on understanding inherited blindness, developing gene therapies for specific mutations, and testing the efficacy of these newly developed procedures on animal models and in clinical trials.

One of the most promising areas of exploration is CRISPR-based gene editing for inherited blindness. According to a 2022 article in the International Journal of Molecular Sciences, CRISPR/Cas9 systems are revolutionary pathways for addressing inherited retinal diseases.

Editas Medicine's Gene Editing Therapy for LCA10

In 2022, Editas Medicine released clinical trial data from a study testing a new gene therapy for inherited blindness that leveraged the CRISPR/Cas9 system. The phase 1/2 clinical trial, BRILLIANCE, assesses EDIT-101, an in vivo CRISPR/Cas9 genome editing medicine for Leber congenital amaurosis.

The Foundation for Fighting Blindness notes  is a group of rare genetic retinal diseases that causes blindness, often from birth. The condition is characterized by photoreceptor dysfunction or degeneration.

The condition impacts vision early on in life, with common symptoms including a lack of visual responsiveness and nystagmus within the first few months. Although sometimes retinas may appear normal upon visual examinations, electroretinogram tests to measure retinal function show little to no retinal activity. Other indications of the condition may include oculodigital reflex, sunken or deep-set eyes, keratoconus, and cataracts.

This set of inherited retinal diseases has been linked to mutations in at least 18 genes, with the most common mutations in the CEP290, CRB1, GUCY2D, and RPE65 genes.

For patients with RPE65 gene-related LCA, Luxturna is an available gene therapy that could address and resolve vision loss; however, none of the other mutations have an FDA-approved gene therapy.

CEP290-gene mutations contribute to LCA10, comprising 20–30% of all LCA cases, making this gene a prime focus area for LCA gene therapies.

EDIT-101 is delivered via subretinal injection that edits the genes in photoreceptors by removing the IVS26 mutation in CEP290 mutant alleles. Early clinical trial data showed the treatment was well tolerated without severe adverse events.

Although the BRILLIANCE trial was designed to enroll 34 patients across 5 cohorts and 3 doses, the condition's rarity posed a barrier for Editas. The company has since discontinued recruitment for the trial, sharing that they need a collaborative partner to continue clinical exploration effectively.

“The results from the BRILLIANCE trial provide a proof of concept and important learnings for our inherited retinal disease programs. We’ve demonstrated that we can safely deliver a CRISPR-based gene editing therapeutic to the retina and have clinically meaningful outcomes,” said Gilmore O’Neill, MB, MMSc., President and Chief Executive Officer, Editas Medicine, in the press release. “While we will not progress EDIT-101 on our own and have made the decision to pause enrollment, we have the patient community top of mind and are looking for a collaboration partner to advance this program.”

BD111

Although the Editas trial has been paused, ClinicalTrials.gov lists one other clinical trial using CRISPR/Cas9 to address blindness. The study, based out of the Eye & ENT Hospital of Fudan University in Shanghai, uses gene editing technology to manage refractory viral keratitis caused by the herpes simplex virus.

The study used BD111, a CRISPR/Cas9 gene editing therapy that eliminates HSV genes, to dose adults and assess “the safety, tolerability, and efficacy of a single escalating doses of BD111 CRISPR/Cas9 mRNA Instantaneous Gene Editing Therapy administered via corneal injection in participants with refractory herpetic viral keratitis.”

Data on this study was published in a 2023 issue of Molecular Therapy, revealing that gene editing for this condition was safe and tolerable.

While refractory viral keratitis is a type of infectious blindness rather than inherited blindness, this study demonstrates CRISPR/Cas9’s ability to address blindness and vision loss.

Preclinical CRISPR Research

Additionally, researchers continue to explore how they can leverage gene editing to manage inherited vision loss. For example, a 2020 paper in Investigative Opthalmology and Visual Science discussed in vivo CRISPR-based gene editing for X-linked retinitis pigmentosa in mouse models.

In mouse models that mimicked retinitis pigmentosa GTPase regulator (RPGR)-related X-linked retinitis pigmentosa, researchers used gene editing technology to address mutations in the RPGR gene. This approach resulted in the restoration of retinal structure and function, improving the retina's treated area and potentially slowing down further degradation.

A more recent study in the Journal of Experimental Medicine also explored gene editing in retinitis pigmentosa.

In a mouse model of retinitis pigmentosa, researchers used a dual AAV system to deliver gene editing technology and correct the disease-causing mutation in the retinas. This restored photoreceptors and produced functional phosphodiesterase 6b, improving vision. The treated mice showed positive responses in various vision tests, demonstrating the effectiveness of our approach in preventing vision loss caused by RP-associated gene mutations.

These are just some examples of ongoing efforts to use gene editing technology to address blindness. However, the International Journal of Molecular Sciences article notes that some challenges persist in CRISPR-based gene therapies for blindness, including delivery, specificity or precision, and off-target concerns.

It's important to note that CRISPR-based gene therapies for blindness are still in the early stages of development, and clinical trials are ongoing to evaluate their safety and efficacy. CRISPR gene editing is rapidly advancing, and further research and clinical testing are needed to determine these therapies' long-term effects and potential.