Gene Therapies for Retinal Diseases Head to Clinical Trials

A rash of clinical trials in the fight against vision loss highlights the promise and peril of genetic therapies. We may be entering an era of gene therapies as long-lasting cures for some of our worst diseases, but many technical problems remain in the search for solutions.

One area in which researchers are making progress is inherited retinal diseases, a large group of monogenic conditions that cause vision loss in around 4 million people worldwide. Later-life causes of blindness that affect hundreds of millions of people globally are also ripe for better, genetic-based therapies.

One recent example is a first-in-human study published in The Lancet of a gene therapy for children with AIPL1-Leber congenital amaurosis. Although not a clinical trial, the study found significant and sustained visual gains in early-onset retinal dystrophy caused by a deficiency in the AILP1 gene, which plays an essential role in the development of photoreceptors. 

This is just one of many ongoing studies and clinical trials to find new ways to treat and prevent blindness caused by inherited retinal diseases.

What are inherited retinal diseases?

Inherited retinal diseases cause vision loss, color blindness, and light sensitivity. They can range from mild to severe and develop early in childhood or later in life. There is no cure for inherited retinal diseases and limited treatment options for many rare diseases. 

The eye’s development and functioning are so complex—more than 300 genes contribute—that there are potentially thousands of mutations that could be targeted for gene therapy. Some of the most common causes, and likely targets of new therapies, are gene variants in CEP290, GUCY2D, CRB1, AILP1, and RPE65.

In the past few years, researchers have published remarkable progress in genetic therapies to slow disease progression and improve vision in these rare genetic disorders, many of which have now entered Phase 1/2 and Phase 3 clinical trials.

Gene technologies are being leveraged 

     

There is no one way to design a gene therapy today. Accessing the cells and appropriately targeting gene therapies can be difficult in solid organs, but the eye is unique. In some cases, injecting the gene therapy into the aqueous humor at the front of the eye is enough to reach the target cells. Others may need surgery to deliver therapy to the retinal cells in the back of the eye. 

Researchers are testing several technologies to deliver a gene or gene editing tools to the eye. The most well-studied approaches to gene therapy are adeno-associated virus (AAV), adenovirus (AdV), and lentivirus vectors (LV). These modified viruses carry genetic material into cells. One issue with this technique is that some people already have antibodies against these viruses. 

The genetic therapy Luxturna, approved by the U.S. FDA in December 2017, uses an adeno-associated viral vector to treat retinitis pigmentosa caused by mutations in the RPE65 gene. Because this mutation is relatively rare, only a small number of patients benefit from the treatment. 

Another option for a gene therapy delivery system is naked antisense oligonucleotides. For example, results from the Phase 1/2 clinical trials of ProQR Therapeutics’s RNA-based drug Sepofarsen for severe early-onset retinal degeneration, published in Nature Medicine, showed significant improvements in visual acuity and retinal sensitivity. The drug corrects splicing defects in CEP290 mRNA, turning the cell’s defective copy into a working mRNA.

Targeted versus general gene therapies

When treating an inherited disease, the target is often the defective gene or mRNA, but not always. Some therapies deliver other genes to reduce disease progression. The most common existing treatment for retinal diseases is blocking vascular endothelial growth factor (VEGF) in age-related macular degeneration (AMD). 

“We've got an anti-VEGF product that we inject every six weeks, and it works well. But for the patient, boy, having an eye injection every six weeks isn't much fun,” Ian MacDonald, MD, MSc CM, director of the Department of Ophthalmology at the University of Montreal. “The gene therapies for AMD are trying to deliver an anti-VEGF product that stays around.”

This treatment could be applied to a wide variety of retinal diseases. Ideally, one treatment with gene therapy would replace regular injections. For example, Regenxbio’s RGX-314 delivers a gene coding for a monoclonal antibody fragment designed to neutralize VEGF in the retina. Trials showed that the treatment greatly reduced the need for injections of anti-VEGF antibodies.

Gene editing versus gene addition

Traditional gene therapy adds a whole gene to the target cell. Newer CRISPR- and RNA-based technologies have enabled the editing of existing genes, leading to new and exciting therapies. Gene addition involves introducing a new, healthy gene copy into a cell. This can compensate for a faulty or missing gene. Gene editing involves precisely altering the existing genes within a cell. This could mean correcting a faulty gene or disabling a gene that causes disease.

For example, a recent Phase 1/2 trial published in the New England Journal of Medicine showed that CRISPR-Cas9–based gene editing is safe and effective for treating severe early-onset retinal degeneration caused by a mutation in CEP290. After treatment, most patients in the trial improved measurably on at least one key vision test, supporting further research of gene editing to treat inherited retinal diseases.

The aim is for these therapies to be one-and-done treatments, saving patients from a lifetime of treatments and progressive, unstoppable vision loss.

“This is a precision medicine. You're getting at the heart of the cause of the disease,” said Ben Shaberman, vice president of science communications at the Foundation for Fighting Blindness. “If you're targeting the genetic cause and a person has some retinal structure left, there's a good chance it's going to work.”

The first FDA-approved gene therapy for inherited retinal disease in the US

Voretigene neparvovec (LUXTURNA®) is a groundbreaking gene therapy approved for the treatment of vision loss due to inherited retinal dystrophy caused by biallelic RPE65 gene mutations, a condition that often leads to blindness. LUXTURNA uses AAV to deliver a functional copy of the RPE65 gene to retinal cells, restoring the production of a protein essential for vision. The therapy is administered as a one-time treatment intended for children and adults with sufficient viable retinal cells. It is the first gene therapy for a genetic disease to receive regulatory approval in both the US and EU.

• 2000: Initial research for LUXTURNA led by Jean Bennett, MD, PhD, and Albert M. Maguire, MD, at the UPenn’s Perelman School of Medicine and Scheie Eye Institute. They then joined forces with Katherine A. High, MD, a gene therapy pioneer who directed the Center for Cellular and Molecular Therapeutics.
• 2013: Children's Hospital of Philadelphia (CHOP) founds Spark Therapeutics to accelerate the development of gene therapies, including LUXTURNA.
• 2017: The U.S. FDA approves LUXTURNA for the treatment of vision loss due to inherited retinal dystrophy caused by RPE65 mutations.
• 2018: Spark Therapeutics enters a licensing agreement with Novartis for the commercialization of LUXTURNA outside of the US.
• 2024: The European Commission approves LUXTURNA for use in children and adults across the EU and associated countries.