With no time to lose, parents drive CMT4J gene therapy forward

CMT4J
Talia Duff’s disorder, CMT4J, is a rare form of Charcot-Marie-Tooth. It has been modeled in mice that will soon undergo a test of gene therapy, largely through her parents’ behind-the-scenes work.

In honor of Rare Disease Day (Feb. 28), we salute “citizen scientists” Jocelyn and John Duff.

When Talia Duff was born, her parents realized life would be different, but still joyful. They were quickly adopted by the Down syndrome parent community and fell in love with Talia and her bright smile.

But when Talia was about four, it was clear she had a true problem. She started losing strength in her arms and legs. When she got sick, which was often, the weakness seemed to accelerate.

Talia was initially diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an autoimmune disease in which the body attacks its own nerve fibers. Treated with IV immunoglobulin infusions to curb the inflammation, she seemed to grow stronger — but only for a time. Adding prednisone, a steroid, seemed to help. But it also caused bone loss, and Talia began having spine fractures.

“We tried a lot of different things, but she never got 100 percent better,” says Regina Laine, NP, who has been following Talia in Boston Children’s Hospital’s Neuromuscular Center the past several years, together with Basil Darras, MD.That’s when we decided to readdress the possibility that it was genetic.”

Talia had tested negative for inherited nerve disorders in the past, but her family agreed to get more comprehensive testing. Last year, at age 10, Talia was diagnosed with Charcot-Marie-Tooth disease — an extremely rare, severe form known as CMT4J. Only about two dozen cases were known worldwide.

“Getting the diagnosis was sort of a double-edged sword,” says Talia’s mother Jocelyn. “You’re handed a diagnosis that has no treatment or cure. But now, we at least had something and could try to find answers.”

Fig4 gene CMT4J
The Fig4 gene, located on chromosome 6, encodes a protein that seems to aid the survival of neurons; it helps regulate the movement of vesicles, small sac-like structures that transport substances within cells.

Wearing a clinician hat

Jocelyn and John, her husband, lost no time. Talia had fallen and fractured her right leg in the summer of 2015, which seemed to accelerate her condition. Her arms now hung helplessly at her sides.

“We couldn’t sit back and watch our kiddo get weaker and weaker without doing anything,” says Jocelyn. A physician assistant by training, she delved into the available research papers. “There was a part of me that didn’t want to read about the possibilities. I had to take off my parent hat and wear my clinician hat.”

The search led to Jun Li, MD, PhD at Vanderbilt University, who met Talia last May. Li envisioned a potential cure for CMT4J: gene therapy. Millions of copies of a harmless virus called a vector would carry healthy copies of the mutated gene — known as FIG4 — into Talia’s cells. If her cells gene successfully took up the gene, it could potentially halt or even reverse her weakness. But turning this idea into reality could take eight to ten years, Li said.

That wasn’t fast enough for the Duffs.

Parent-driven research

Talia with her parents and sister Teaghan (Kara Swenson Photography)

In June, Jocelyn and John formed CureCMT4J and began fundraising. With Li, they gathered a team of about eight researchers for a meeting in September in Bethesda, Maryland — the world’s first-ever symposium on CMT4J.

Each researcher gave a presentation. Some had never heard of CMT4J, but were there because they were using gene therapy for a similar rare disease. At the end, all agreed that gene therapy was worth pursuing for Talia’s condition.

In a recent conference call with the foundation’s scientific advisory committee, the Duffs got exciting news: Researchers at The Jackson Laboratory had created mice with the same genetic defect as Talia’s. These mice will provide the first testing ground for CMT4J gene therapy.

“The vector is being made at the University of North Carolina, and they hope to inject the mice in April or May,” says Jocelyn. “Our researchers feel they will have a preliminary proof of concept within six or eight weeks after the injection.”

“It’s just a matter of time”

Talia now needs a wheelchair and has difficulty feeding herself. The disease has crept into her respiratory muscles, so she uses a nebulizer and a device to help her cough up her secretions when she has a cold. She continues to receive care from Laine, Darras and multiple specialists at Boston Children’s.

But she refuses to stop living life fully.

“Talia is a really neat kid,” says Jocelyn. “She loves school, has lots of great friends, loves to read, loves music, loves to dance in whatever capacity she can, loves to swim and kayak. We’ve even tried adaptive skiing. She has an incredible amount of empathy and resilience, and she’s usually able to put an incredibly happy face on most everything.”

To date, CureCMT4J has raised about $118,000 through corporate and private donations. But since a small clinical trial will cost an estimated $1 to $3 million, the Duffs hope to interest biotech, pharma and other corporate donors in funding or sponsoring further research.

“We really feel that the science is there, and that it’s just a matter of time before we have enough preclinical data to move forward,” she says. “We believe the science is translatable to thousands of other diseases that could also be treated with gene therapy. We and other parent-driven foundations are hopefully laying the groundwork so this will become easier and less expensive.”

Learn more about CureCMT4J, care at the Neuromuscular Center at Boston Children’s and other citizen scientists who are making a difference.