#IARC2017 – Chondrial Looks to Move Protein Replacement Therapy into FA Trials, Chief Scientific Officer Says

Protein replacement is one of several cutting-edge approaches to treating ataxias that generated a buzz at IARC 2017, the International Ataxia Research Conference that concluded Saturday in Pisa, Italy.

One scientist helping to pioneer this approach is Mark Payne, a pediatric cardiologist, mitochondria expert and Friedreich’s ataxia (FA) trailblazer at Indiana University School of Medicine.

Payne has been working on protein replacement for 17 years, he said in an interview with Friedreich’s Ataxia News at the IARC conference, which ran Sept. 27-30. (The taped interview, in full, follows this article.)

His team’s work has advanced to the point that Payne helped form a company, Chondrial Therapeutics, to take it to the next level: obtaining regulatory approval of the technique and commercializing it.

Payne, chief scientific officer at Chondrial, said the company is in the early stages of laying the groundwork for Phase 1 and 2 clinical trials of its potential treatment, known as CTI-1601. The U.S. Food and Drug Administration designated the potential therapy an orphan drug in August.

The idea behind protein replacement therapy is “simply replacing the protein that’s missing in mitochondria,” the cell component that produces energy, Payne said. In the case of FA, that missing protein is frataxin. Without it, cells fail to generate the energy that important organs need to function properly.

“There are specific organs inside the body that use a ton of energy,” including the heart, portions of the brain and the eyes, Payne said. “Without adequate mitochondria function, over time these organs, these specialized tissues, will fail and then the disease [FA] becomes apparent.”

Abnormalities in the gene that produces frataxin protein are the reason the body fails to create enough of it.

Two other approaches to generating the missing frataxin focus on overriding the faulty gene that is unable to produce it. One is viral gene replacement therapy and another is gene editing — correcting the defects in the gene so that it works properly. Both approaches were also widely discussed at the Pisa conference.

As an example of viral gene therapy, Payne said Dr. Hélène Puccio of Inserm used a non-infectious virus to deliver a normal frataxin-producing gene to heart cells in mice that had been genetically engineered to mimic FA. The gene replaced the faulty one that had been unable to produce the protein.

Friedreich’s Ataxia News had a chance to interview Puccio at IARC 2017; read more about it at this link.

The challenge of protein replacement, Payne said, is getting the protein “from an injection site or from an oral intake or IV infusion area to where it needs to go in the body and then where it needs to go inside the cell” — that is, to mitochondria.

There are a number of ways to do this, he said. The approach he’s taken is “to create a replacement protein and engineer it so that it will cross all the membranes it needs to pass through and move into mitochondria.”

Payne decided to pursue protein replacement after Dr. Steve Dowdy’s team at Washington University in St. Louis used a test protein to show that the technique could work in mice.

“That was pretty exciting,” Payne said.

He had mitochondria expertise, so he decided to focus his protein replacement work on frataxin.

To test the protein replacement therapy that he developed, Payne collaborated with Puccio, using the mouse model she created to mimic FA. He built on that work by creating a synthetic frataxin protein and using a protein fragment called a transactivator of transcription, or TAT, to deliver it to mitochondria.

When his team tried their protein replacement therapy in Puccio’s mice, the animals “lived much longer and their heart function was much better,” Payne said.

Although the symptoms that people most associate with Friedreich’s ataxia are movement and balance problems, the major cause of death is heart malfunction, doctors say.

An encouraging part of Payne’s protein replacement work was that “we were putting a human protein back into a mouse, which was not a normal protein for the mouse to have, and yet it still would work,” he said.

“It didn’t rescue them all the way [from FA symptoms], but it did rescue them enough” to show that protein replacement would work in the disease, he said. He added that the heart deterioration that affects Friedreich’s ataxia is “very silent, so it’s important for a patient with FA to see a cardiologist.”

Unfortunately, there’s no treatment yet for the cardiac and brain dysfunction in FA. “It’s going to take either protein replacement therapy, or viral gene therapy, or even perhaps another therapy” to address the full problem, he said.

Payne’s breakthroughs have led to several patents on his protein delivery system and paved the way for grants from the National Institutes of Health and the Friedreich’s Ataxia Research Alliance (FARA) to continue his work.

Payne is now a scientific advisory board member of FARA, which was one of the main organizers of the IARC conference, along with Ataxia UK and the Italian ataxia organization GoFAR.

Although he has shown that protein replacement works in mice, there’s a big leap to demonstrating that it works in humans.

Many therapies fail to make the transition from working in laboratory cell cultures and in animals to working in patients.

“This work has moved from pure basic science to what is called translational science,” or the bridge between having it succeed in mice and having it succeed in humans, Payne said.

As he looks forward to seeing whether his protein replacement approach works in humans, he continues to watch for new developments in mitochondrial and Friedreich’s ataxia research.

One of the presentations that impressed him at the IARC conference was Zhen Yan’s study of the ability of exercise to improve the mitochondrial function and maintain the muscle strength of mice with the disease. Yan is a University of Virginia professor.

“This really provided some of the basic science evidence that exercise is beneficial with this disease,” Payne said. “This could allow us to do clinical trials showing that exercise can help FA patients.

“This won’t cure the disease,” he added, “but it may help them with mobility and to avoid problems later on in life.”

His enthusiasm about Yan’s research underscored the importance, for scientists and others working in the field, of conferences like IARC that encourage collaboration and an exchange of ideas.

Watch our full interview with Payne here: