Can gene therapy treat vision loss?

Since the approval of the first-ever gene therapy for blindness, there has been a wave of biotechs developing gene therapy treatments with the potential to cure different forms of genetic vision loss. 

Luxturna became the first gene therapy for inherited blindness to receive the green light from the U.S. Food and Drug Administration (FDA) back in 2017. About a year later, the therapy was approved in Europe. This was a significant milestone for innovation in the treatment of blindness, but also for gene therapy, as Luxturna was also the first in vivo gene therapy – a treatment that is delivered directly into the patient’s cells rather than extracting and modifying the cells before reinjecting them.  

Luxturna was developed by the U.S. company Spark Therapeutics, which was acquired by Swiss pharma giant Roche in 2019. The therapy is designed to treat patients with mutations on a gene called RPE65, which encodes a retinal protein necessary for the eye to respond to light. The treatment consists of injecting a healthy copy of the gene to restore the missing protein. A single injection in each eye has been shown to be enough to improve vision for at least three years.

While its exorbitant price has stirred controversy, the success of Luxturna has set a precedent for many other gene therapies in development that are aimed at fixing the many other genetic mutations that cause blindness, with multiple approaches being put forward.

How does gene therapy for vision loss work?

Gene therapy consists of providing the patient with a functional copy of a gene that is missing or mutated. In the case of Luxturna, a copy of the RPE65 gene is delivered to the patient’s eye using a viral vector. The virus is modified to eliminate its capacity for infection and introduce a functional gene that can be used by the patient’s cells to generate a functional protein.

This form of treatment is particularly suited to treat the eye. First of all, the eye is an immune-privileged area of the body where the immune system has restricted access. This prevents immune reactions against the viral vector used to deliver the treatment. In addition, the cells of the retina can keep this DNA functioning for longer than other cells in the body. This means that a single dose injected into each eye can be enough to restore sight in the long term.

“These cells don’t renew or mutate, and therefore should conserve DNA expression all their lifetime,” said Bernard Gilly, co-founder of the French company GenSight. “A study on neurons in monkeys showed up to eight years of expression of the protein.”

Treating different forms of blindness: biotechs on a mission

Following Luxturna, many biotech companies are advancing a variety of technologies to correct different mutations causing vision loss. Among the advancing gene therapy biotechs is New York-based MeiraGTx. A recent study revealed that 11 children who were blind at birth gained visual acuity, which is a measure of how clearly you can see at a specific distance, after they received MeiraGTx’s investigational gene therapy rAAV8.hRKp.AIPL1. All the participants of the trial had a condition called Leber congenital amaurosis type 4 (LCA4), which is a severe, inherited eye disorder characterized by profound vision loss.

“LCA4 is one of the most severe forms of inherited blindness, and the results from these 11 young children are truly remarkable. The improvements demonstrated are unrivaled in treatment benefit compared to any ocular gene therapy in any IRD. These improvements extended outside the meaningful effects on vision, and result in life-changing benefits in all areas of development, including communication, behavior, schooling, mood, psychological benefits, and social integration.” Alexandria Forbes, president and chief executive officer (CEO) of MeiraGTx, had said in a press release.

Having bagged orphan drug and rare pediatric disease designations from the FDA, MeiraGTx looks to expedite the approval of the gene therapy as it works with regulators worldwide to provide access to babies born with LCA4.

Vision loss is also one of the major, progressive symptoms of X-linked retinitis pigmentosa (XLRP). It is caused by mutations in genes located on the X chromosome, which means the condition predominantly affects those assigned male at birth. Florida startup Beacon Therapeutics has come up with a gene therapy to potentially correct this mutation. 

The therapy laru-zova improved key measures of visual function, such as low luminance visual acuity and eye sensitivity, according to interim results posted last month. 

It was able to do so as it is designed to restore the natural function of the light-sensitive nerve cells in the eyes – rods and cones – by transporting a functional copy of the retinitis pigmentosa GTPase regulator (RPGR) gene into the eye. Abnormalities in the RPGR gene play a role in vision loss linked to XLRP.

Atsena Therapeutics raises funds for gene therapy program for XLRS

Meanwhile, it looks like American biotech Atsena Therapeutics has been doing well on the gene therapy front, following its $150 million fundraise in April. Its XLRS therapy, ATSN-201, delivers a normal copy of the retinoschisin gene to the eye with the help of a new capsid called AAV.SPR. Retinoschisin is key to preventing the retina from splitting into layers, resulting in poor vision. The therapy helped close the splits in seven out of nine patients in the phase 1/2 trial. The results were statistically significant in visual acuity, according to the press release.

“These findings represent a significant breakthrough, validating the use of our novel capsid to effectively treat inherited retinal disease and informing the safest and most effective path forward for Part B of the study, which is already underway. We look forward to advancing ATSN-201, which is on track to be the first gene therapy approved for XLRS,” said Kenji Fujita, chief medical officer (CMO) of Atsena Therapeutics.

Adverum Biotechnologies’ ixoberogene soroparvovec shows promise in wet AMD treatment

Like XLRP, wet age-related macular degeneration (AMD) can also lead to vision loss. Wet AMD accounts for approximately 10% of all AMD cases but results in 90% of legal blindness, according to a report by Macular Degeneration Research.

There are several gene therapy specialists working to cure the condition, one of which is California-based Adverum Biotechnologies. In a phase 2 trial, its gene therapy ixoberogene soroparvovec was found to significantly reduce treatment burden. 

It reduced the anti-vascular endothelial growth factor (anti-VEGF) injection rates by 90% among the 19 patients in the low-dose group and 94% of the 20 patients in the high-dose cohort. At 26 weeks, ixo-vec demonstrated injection-free rates of 68% for the low-dose group and 85% of the patients in the high-dose arm.

Adverum’s pipeline is fully focused on treating eye diseases, however, its previous efforts to treat diabetic macular edema, a serious complication of diabetes that can cause blindness if untreated, failed after a patient went blind when injected with ixoberogene soroparvovec – back when the gene therapy was known as ADVM-022.

Wet AMD: AbbVie, Regeneron, and 4DMT trial gene therapies in clinic

Besides, one of the biggest gene therapy programs ever run is a wet AMD trial that evaluated big pharmas AbbVie and Regeneron’s ABBV-RGX-314. The candidate is designed to reverse vision loss by inducing an anti-VEGF response. Following a phase 1/2a dose-escalation study, the companies are now enrolling patients in a U.S. and a global trial, as they plan to apply for regulatory approval in Europe and the U.S. later this year. 

Similarly, 4D Molecular Therapeutics’ 4D-150 is another contender in the space, now in phase 3 trials. In fact, it doubled down on 4D-150 development, having culled two of its other programs to direct the funds towards treating wet AMD with the gene therapy.

Meanwhile, one biotech that has been here all along is the Parisian company GenSight. Having faced various ups and downs over the past few years, with cash runway issues as well as snags in the development and possible approval of its gene therapy LUMEVOQ, it has now been saved with a €0.9 million ($1.03 million) funding that closed in March. GenSight had sent off LUMEVOQ’s approval application to the European Medicines Agency (EMA) but then withdrew it in 2023 after the Committee for Advanced Therapies (CAT) failed to support the therapy’s potential approval for Leber hereditary optic neuropathy, a vision loss-causing inherited condition that occurs when the optic nerve is damaged. 

Gene therapies for vision loss: the limitations

Despite the great potential of gene therapy, one of its limitations is that each treatment can only fix a single gene. That significantly reduces the number of people that can benefit from each gene therapy when considering diseases like retinitis pigmentosa, which can be caused by mutations in 60 different genes.

Moreover, because gene therapies require viable target cells to treat the condition, their efficacy begins to decline when these cells face degeneration. 

Another challenge of designing gene therapies to address vision loss is the limited cargo capacity of the carrier itself – the carrier typically being adeno-associated virus (AAV). These can take loads of around 5 kb – the measure for the length of DNA. As genetic blindness tends to be caused by mutations in sizable genes, such as ABCA4 gene associated with Stargardt disease and the MYO7A gene linked to type 1 Usher syndrome, which are about 7 kb and 87 kb, respectively, they don’t fit into AAVs. 

Scientists have thought of a strategy to overcome this, and it is being tested. It involves splitting the large genes into two to be carried by vectors, and after they are injected into the eye, they recombine to form the gene.

Sounds great, but how much does it cost?

Developing a gene therapy is expensive, making it unfeasible to develop one for each mutation, especially for extremely rare mutations. And of course, as a result, gene therapy is far from cheap. In Germany, Luxturna costs a whopping €345,000 ($394,290) per eye, and in the U.S., it’s even higher at about $425,000. That makes Luxturna among the most expensive drugs in the world, along with other gene therapies such as Sarepta Therapeutics’ Duchenne muscular dystrophy therapy Elevidys, Novartis’ Zolgensma for the muscle weakness condition spinal muscular atrophy, and bluebird bio’s Zynteglo to treat beta-thalassemia, a genetic blood disorder.

We can expect upcoming gene therapies to have similar price ranges, especially for those treating rarer forms of genetic blindness. These prohibitive figures might mean that not everyone will have access to curative treatments.

To alleviate some of the costs for gene therapies, some companies are spacing out the payment over time and conditioning the payment to the therapy working. For example, Spark Therapeutics set up a payment scheme for Luxturna in the U.S. that is based on the outcome of the gene therapy. Partial refunds, depending on whether the therapy works in the short term (30-90 days) or the long term (30 months), were introduced soon after it hit the market.

CRISPR and new early-stage gene therapies: a brighter future in sight 

In the coming years, we can expect more and more gene therapies treating vision loss to enter the market to provide curative solutions for many patients in need. One of the most anticipated technologies is CRISPR-Cas9, which has revolutionized the world by making gene editing simpler than ever.

With CRISPR it would be possible, in theory, to fix a mutation causing blindness directly in our retinal cells. Although the technology is still in the early stages and most CRISPR treatments are directed at other conditions, a Harvard University study showcased the safety of CRISPR gene editing and found that it can improve vision in some people with inherited blindness last year.

Other genetic medicines are also in the making. Just today, Barcelona-based SpliceBio announced that it raised $135 million in series B financing to fund the development of its lead program SB-007 for Stargardt disease. 

Stargardt disease is an inherited retinal disorder caused by mutations in the ABCA4 gene that leads to progressive vision loss and blindness. There are no approved treatments for it yet, but SpliceBio wants to change that. SB-007 is designed to produce a functional copy of the ABCA4 protein to treat all patients regardless of their specific ABCA4 mutation.

“With compelling data for its lead program, SB-007, and a highly differentiated platform, we are excited to support SpliceBio as it tackles a fundamental challenge for genetic medicines. By enabling the delivery of large and complex genes through its novel AAV vector protein splicing technology, SpliceBio has the potential to make a significant impact on the field of gene therapy and to deliver best-in-class therapies to patients,” said Laia Crespo, partner at Sanofi Ventures, which co-led the financing round.

A few other young companies in Europe have cropped up in the past decade to advance their genomic medicines to address vision loss. Parisian companies Coave Therapeutics and SparingVision are working on therapies, with the latter’s SPVN06 launching phase 2 trials for geographic atrophy, a late-stage, more severe form of AMD, last year. As for preclinical development, British startup Ikarovec has created IKAR-001 to also treat geographic atrophy. 

The use of gene therapy will likely be limited to a small number of patients with specific mutations and rare diseases, and it will probably be a while before it can become a mainstream treatment that can really cure multiple causes of blindness. But as time goes on, hopes that the technology can treat a vast group of diseases are slowly becoming a reality. 

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