In pursuit of three gene therapies for a rare inherited disease

Newswise – When neurobiologist David Corey showed up at a rare disease conference in 2017, he had no idea he’d be in a race against time to develop a cure for it.

The conference was for Usher syndrome type 1F. Patients with this disease have a gene mutation that causes them to be born deaf and gradually lose their sight as they grow older. The Bertarelli Professor of Translational Medicine at Harvard Medical School’s Blavatnik Institute had devoted decades to studying the defective gene in a different context.

So when Corey happened upon an announcement about the Usher 1F conference in Boston, he knew he had to attend.

There, he was introduced to Eliot Chaikoff, chief of surgery at Beth Israel Deaconess Medical Center and Johnson & Johnson professor of surgery at HMS, his wife, Melissa, and their grown daughters, Rachel and Jessica, who both have Usher 1F. The Chaikofs organized the conference through a nonprofit research collaboration they founded to find a cure for the blinding part of the disease.

Meeting the Chaikoffs, and especially Rachel and Jessica, made Corey want to help.

“We really felt that we know so much about this gene that if we don’t try to do something about the disease, who else is going to,” Corey said.

Six years later, Corey’s lab has three candidate gene therapies for Usher 1F blindness. Each takes a different approach to correcting the disease-causing mutation.

Researchers are now testing the therapies in animal models and are confident that at least one will move to human clinical trials to become a successful treatment.

Defining the problem

Usher 1F is a particularly severe form of Usher syndrome, in which a gene mutation causes cells in the eye and ear to stop producing an essential protein. Rachel and Jessica’s gene mutation is most common in the Ashkenazi Jewish community.

People with Usher 1F are usually born deaf and lack the ability to maintain balance. They develop an eye disease called retinitis pigmentosa, which causes progressive vision loss as the retina degenerates. Night vision is often the first to disappear, followed by peripheral vision. For Jessica, that means giving up driving and getting a service dog to help her navigate the world around her. Eventually, people go completely blind.

“Everyone has a unique experience with Usher 1F, but one of the biggest challenges for me is slowly losing my independence as I lose my sight,” Jessica said.

Like many people with Usher 1F, Rachel and Jessica have benefited from cochlear implants, which have improved their ability to hear and communicate. However, the Chaikoffs learned when their daughters were diagnosed that there was almost no research into the condition and virtually no treatment to treat it, so in 2013 they founded the Usher 1F Collaborative.

“There were basically zero research groups working on this particular problem — nothing, nobody,” Elliott said.

A call to action

While the Chaikoffs were looking for answers, Corey’s lab in the HMS Department of Neurobiology was studying a protein called protocadherin-15 and its role in deafness.

The researchers found that protocadherin-15 in the inner ear helps sensory receptors called hair cells convert mechanical vibrations into electrical signals that the brain interprets as sound. Without protocadherin-15, the conversion does not occur and the brain cannot detect sound.

They also found protocadherin-15 in the light-sensing cells, or photoreceptors, of the eye. However, they weren’t sure of its exact function there, nor did they know why people who lack the protein in their eyes lose vision over time.

During the research, Corey learned that a mutation in the gene that makes protocadherin-15 in Usher 1F causes cells in the ear and eye to stop producing it.

Connecting with the Chaikoffs gave Corey new motivation for his research and reinvigorated the family’s search for a cure.

“Because David understood the gene so well, he basically jumped off the research site and hit the ground running,” says Melissa, who is president of the Usher 1F Collaborative.

“For the first time, we felt like we had someone who could really make a difference on this particular issue,” Elliott added.

Terrible job

Corey’s lab decided to focus on the blindness aspect of Usher 1F, in part because patients are born profoundly deaf and lack hair cells, making it unlikely that the therapy could restore their hearing. However, they are born with normal vision that gradually deteriorates, allowing for timely intervention to preserve their vision.

The team found the perfect point person in Marina Ivanchenko, an HMS neurobiology instructor who joined the lab to learn about gene therapy for deafness, but is also quietly an ophthalmologist and eye surgeon.

“Marina has been absolutely central to this project because she understands both the hearing and the blind aspects of this disease,” Corey said.

The researchers decided that the way forward would be to develop gene therapy that would either replace or repair the defective DNA encoding protocadherin-15. Such therapy, delivered inside the cells of the eye, would allow the cells to produce the missing protein.

But the team faced a big challenge. Protocadherin-15 is a huge protein, and the DNA that codes for it is too large to fit inside a typical delivery vehicle, a tiny capsule made from a non-infectious virus.

With Rachel, Jessica, and thousands of others with Usher 1F on the clock, the team knew the best hope for rapidly developing an effective gene therapy would be to work on three different potential solutions simultaneously.

Three shots on goal

The logistics of such a project are daunting.

Because there is no good mouse model of Usher 1F blindness, Corey and colleagues began testing in a mouse model of deafness whether each therapy could restore protocadherin-15 production. Then they moved on to the zebrafish, which offers a better model for progressive blindness. Trials are ongoing in human eye cells grown in dishes, followed by tests in non-human primates. Only then can the therapy be deemed safe and effective enough for a human clinical trial.

“The project was extremely complex because we were testing three different strategies in two different organs and four different species,” Corey said. “Every time you add something, it multiplies the effort.”

However, the Corey lab, supported by funding from HMS and the Usher 1F Collaborative, has made significant progress in all three strategies;

• The most promising so far is mini gen — a truncated but still functional version of the protocadherin-15 gene that fits easily inside the viral capsule that carries the DNA into the cell. Not recently studyThe researchers have shown that their minigene can restore hearing in mice, and early experiments in zebrafish have shown that it can also restore sight.

• The second strategy, called dual approach, involves cutting the DNA in half. Each half is small enough to fit into the viral capsule. Once inside the cell, the halves reassemble and can begin making the full-length protein. The approach has been used for other genes, Corey noted, and appears to be a good fit for protocadherin-15. Researchers have tested this approach in mice and are beginning to test its safety in nonhuman primates.

• The final strategy involves putting gene editing tools into the viral capsule instead of loading it with a replacement gene. Once inside the cell, the gene editors will correct the mutation in the protocadherin-15 gene. Many mutations cause the condition, but researchers are designing tools to correct the most common, R245x. Recently, scientists showed that their approach can reverse hearing loss in mice.

Corey and his colleagues, including Marcos Sotomayor at Ohio State University and Arthur Injikulian with Massachusetts Eye and Ear Usher 1F.

“This is an outstanding example of how basic science can be translated into therapy,” Elliott said. “The progress David has made in a very short period of time is remarkable.”

The lab has plans to partner with a biotech company that will continue to work on any treatments that pass initial testing.

Finding hope

If either strategy clears the hurdle of animal testing, the next step will be clinical testing. However, there is another challenge. Because Usher 1F is an orphan disease, meaning it affects fewer than 200,000 people in the United States, it will be difficult to enroll enough people in randomized controlled trials.

To overcome this challenge, the Usher 1F Collaborative initiated a natural history study of vision loss in humans with Usher 1F. The study will follow participants for four years to assess how their vision loss progresses naturally, essentially establishing a control group ahead of time for the clinical trial. That way, if and when the trial takes place, all participants can receive the therapy.

“We’re going in parallel with David’s research so that when the natural history study is complete, we’ll be ready for the clinic,” Melissa said.

It’s not clear which treatments will succeed, or when, but the possibility that they could make a tangible difference in people’s lives keeps Corey, Ivanchenko and others motivated as they work long hours in the lab.

And Corey’s three shots on goal were too many. Eight other groups at universities in the US, Canada and Australia are also working on a treatment for Usher 1F, thanks to the collaboration’s funding.

“There are a lot of patients and families whose world is about to go dark, and they need everyone’s best ideas,” Elliott said.

“I keep telling myself that there will come a time when I can finally stop letting my life revolve around Usher,” Jessica said. “Seeing the research is what keeps me sane. it’s what gets me through the day.”