Frataxin-producing Compound’s Journey from Basic Science to Possible Clinical Trial: One Researcher’s Story

A dozen years ago, Joel Gottesfeld became intrigued with the conclusion of a paper he was editing for the Journal of Biological Chemistry.

The article that the Scripps Research Institute scientist was reviewing dealt with the gene that codes for frataxin, an essential protein that’s missing in Friedreich’s ataxia.

The authors, frataxin experts Bob Wells and Marek Napierala, offered an explanation for frataxin’s absence: A mutation in the FXN gene, which other scientists had identified, causes the gene to adopt an unusual DNA structure. And that structure silences the gene, preventing frataxin production.

The paper’s conclusion “basically said something like, wouldn’t it be neat if you could find a pharmacological agent, a small molecule, to turn the frataxin gene back on,” Gottesfeld said in an interview with Friedreich’s Ataxia News. 

Gottesfeld was attending the International Ataxia Research Conference in Pisa, Italy, in late September. A key theme of the conference was that collaboration is crucial in developing treatments for Friedreich’s ataxia and the dozens of other ataxias. And Gottesfeld’s development of a compound that could treat the disease is a story of collaboration.

He said he had been interested in the interplay between the makeup of chromosomes — which are structures that contain genes — and how the body regulates genes since his graduate school days.

So the question posed by the frataxin article’s conclusion prompted him to decide: “That’s what I want to do.”

It was a turning point in his career. It led to him and others at Scripps and its corporate partner BioMarin Pharmaceuticals who are working to develop a chemical compound they hope will turn on frataxin production in FA patients. Clinical trials are likely on the horizon, he said.

The path between Gottesfeld’s decision to develop a potential frataxin-triggering compound and a possible springboard to clinical trials is instructive, because it not only shows the twists in the therapy development process and the collaboration that’s necessary, but also how long the process can take.

The first step, Gottesfeld said, was basic science.

“What my lab and a number of other labs did a decade or so ago was to figure out just what the genetic mutation does to cause the loss of this protein,” he said.

The reason the FXN gene is abnormal in FA is that it contains too many repeats of one of the DNA sequences that make up the gene.

At the heart of frataxin silencing, scientists discovered, was a characteristic of another type of protein that is packaged with the FXN gene.

These proteins, called histones, “can have chemical tags put on them, and these tags either tell the gene whether it’s going to be active or inactive,” Gottesfeld said. “It turns out that the repeats cause the chemical tags to be inactive,” which means they don’t produce frataxin.

“So the idea that we had was to identify small molecules [chemical compounds] that would reverse the tags that say ‘I’m an inactive gene,’ and cause the tags to say ‘I’m an active gene,’” he said.

His team found a commercially available molecule that prompted the gene to become active — but not active enough.

So a chemist in his laboratory, Ann-Kristen Jenssen, tweaked the compound to “show us the path forward to make a molecule that would fully reactivate the silent gene,” Gottesfeld said.

The next step was to test the refined molecule in cell cultures of FA and in mice with the disease. Gottesfeld’s team collaborated on the mouse research with Massimo Pandolfo, who discovered the FXN gene mutation that causes FA and who developed a mouse model of the disease to help study it.

The cell and mouse research showed that the molecule could turn on frataxin production. This meant that it was time to find a corporate partner to work toward a therapy, Gottesfeld said.

A small Boston-area biopharmaceutical company called Repligen became that partner. It improved on the molecule, which it named RG2833, and brought it to a Phase 1 crossover clinical trial in 20 FA patients that concluded in 2013.

The results, published in Annals of Neurology in 2014, “showed that, at least in circulating white blood cells in Friedreich’s ataxia patients, that we could turn the gene back on,” Gottesfeld said.

As the study’s authors put it, results provided “proof of principal for orally administered class I HDAC inhibitor as potential therapeutics for Friedreich’s ataxia.”

“So this was very encouraging,” Gottesfeld said. “But the problem was — and in drug discovery this is very common — there were problems with the molecule. So this was Round One.”

At that point, Repligen decided to get out of drug development and sell its FA therapy development technology to BioMarin, the nation’s ninth-largest pharmaceutical.

Since then, Gottesfeld’s team has been collaborating with the California-based company “on screening a large collection of derivatives of the original compound class.”

After BioMarin decides on a final compound and tests it in cell cultures and in animals, the next step will be to request a clinical trial.

A decision by BioMarin on a final version of the compound is on the horizon, Gottesfeld said.

Gottesfeld said the Friedreich’s Ataxia Research Alliance does an amazing job of facilitating collaboration, introducing him to experts who have helped advance his own research. FARA was one of the main organizers of the IARC conference in Pisa, along with Ataxia UK and the Italian Friedreich’s ataxia organization GoFAR. (GoFAR also helped to support Repligen’s Phase 1 study.)

FARA, particularly, has been a special force in Friedreich’s ataxia, Gottesfeld said.

“Not everybody can do everything” in research, he said. “I know what I can do. I don’t know one end of a mouse from another end of a mouse, so when it comes time to do the mouse model study, I need to collaborate.” FARA introduced him to a number of partners, he said, including Pandolfo.

Gottesfeld has been at the Scripps institute for 40 years, he said. Regulatory approval of a small-molecule therapy that helps people with FA would be a fitting cap to his career.

Meanwhile, his lab will continue working with BioMarin until it makes a final decision on a compound for possible human trials.

“They send us molecules that they have synthesized, and we have this cell model — actually human neurons from patients’ cells — that we test them on,” he said.

His team has put a good deal of work into developing a way to treat FA since he reviewed that journal article 12 years ago.

But if you were to ask him about it, he would likely say it’s been a lot of fun.