Probing the Cause of a Rare Disease
Jacob lab studies CTNNB1 syndrome, a rare genetic disorder affecting mobility and learning.
GSBS faculty member and Tufts University School of Medicine professor Michele Jacob is a neuroscientist, not a clinician, so it is unusual for her to work directly with patients. But when serendipity brought her together with a group of parents whose children have a rare developmental disorder caused by mutations in a gene she was researching, it was a win-win for all involved.
Jacob and her team have been studying the CTNNB1 gene product and its role in the brain for many years. The CTNNB1 gene encodes the beta-catenin protein, which is critical for proper cell development and function. Disruptive mutations in CTNNB1 result in lower-than-normal levels of beta-catenin. Work from the Jacob Lab at the Graduate School of Biomedical Sciences and other researchers have shown that abnormal levels of beta-catenin are high risk factors for autism spectrum disorder and intellectual disability.
It wasn’t until Jacob was contacted by a woman in Italy that she learned even more about disorders caused by beta-catenin dysregulation.
The woman has a daughter who had been diagnosed with CTNNB1 syndrome, a rare disorder that affects 1 in 50,000 people worldwide.
“I was impressed by this woman,” says Jacob. “She has no science training, she told me that she reads the [medical] literature at night and found one of our papers on beta-catenin. Then she told me about her daughter’s disorder.”
Long Road to a Diagnosis
CTNNB1 syndrome is caused by loss-of-function CTNNB1 gene mutations, either complete or partial deletions. It is what’s known as a sporadic mutation, meaning it is not inherited from the parents. The symptoms appear in the first few months after birth, when the children do not hit their developmental milestones. The syndrome was first identified in 2012 and requires gene sequencing for a definitive diagnosis.
Children with CTNNB1 syndrome exhibit a spectrum of learning and motor disabilities. They include intellectual disability, language delays, low muscle tone in the trunk, and high tone in leg muscles, causing spasticity and problems with mobility. Some of the children also have autism.
The woman in Italy ultimately connected Jacob with two families—the Cochrans and the Dashiells—in the New York area, who were in the process of creating a nonprofit to raise funds for research into the syndrome; both have children with CTNNB1 syndrome. Nicole Dashiell and Lauren Cochran had originally connected via a Facebook group for parents of children with the disorder.
Because CTNNB1 is such a rare genetic condition, it can take a long time for patients to be diagnosed accurately.
Typically, babies are perfectly healthy at birth, as was the case with Lauren Cochran’s son, Declan. Starting at around three months old, however, Declan’s parents and pediatrician started to notice that he wasn’t hitting certain developmental milestones. He wasn’t holding his head up properly and he had low muscle tone. “We began physical therapy immediately, but he was delayed to sit up, crawl, and walk. He still struggles with balance.”
After an MRI and even chromosomal testing didn’t turn up anything abnormal, Declan’s neurologist mentioned doing full exome testing, a more comprehensive type of gene analysis than standard genetic testing. She said this was the last step and that they had exhausted all other testing options. Declan was making significant progress but still hadn’t caught up to his peers.
“They told us it was going to be like a needle in a haystack and that they were probably not going to find anything,” says Cochran. “About four or five months later, we got a call from the geneticist, who said ‘you won’t believe it, but we found what it is. It's a mutation in the CTNNB1 gene.’”
Once Cochran learned there are no treatments for the disorder other than physical and speech therapy to treat symptoms, Cochran says she was on “an absolute mission” to find someone willing to research the disorder, with the goal of ultimately finding a treatment to help Declan reach his full potential.
Lauren approached Nicole about joining her in this endeavor. “We thought ‘well, if not us, then who, and if not now, then when,’” says Cochran. In 2019, the two families founded a nonprofit organization called Advancing CTNNB1 Cures and Treatments (ACCT) to raise funds for research on CTNNB1 syndrome.
In yet another fortuitous coincidence, a mother from California (via the mother in Italy) sent Cochran an article that Jacob had written on beta-catenin and intellectual disability. After some back and forth, Cochran invited Jacob to their first fundraiser. Jacob enthusiastically accepted.
“She laid out what her research would involve if she partnered with us,” says Cochran. “She had a plan, and she was passionate about helping us. And we've been funding her research ever since.”
Testing Drug Treatments
The first grant allowed Jacob to create a mouse model with a full body deletion of one CTNNB1 allele. She and her team determined that this mouse line shows learning impairments and reduced muscle strength, resembling the symptoms of the human disorder. Since then, they have been using the mice to identify underlying molecular changes and to test for drug treatments that may be corrective. Jacob is collaborating with medicinal chemists to define safe and effective medications that could raise beta-catenin to more normal levels and increase cognitive and motor function.
In the experiments, one of the drugs corrected beta catenin levels and significantly improved learning abilities and muscle strength in the mouse model of CTNNB1 syndrome.
“What we're seeing in the mouse is that they show reduced muscle strength and motor learning. When we put the mouse on this drug, the muscle grip strength significantly improved, and the cognitive skills came up to wild-type levels,” says Jacob, who also has a grant from the National Institutes of Health for her mouse and human cell studies of CTNNB1 syndrome. “We were amazed. We treated the mice at a young adult age, so we were incredibly excited because this opens up the possibility of treatments for older children."
Before CTNNB1 syndrome was identified, Jacob says, kids were often diagnosed with cerebral palsy and other disorders and are just learning they actually have this syndrome caused by CTNNB1 gene mutations.
Looking ahead, Jacob will be testing these medications for corrective effects in CTNNB1 syndrome patient-derived cells. From there, the hope is that the mouse and human preclinical studies will lay the foundation required to get a pilot clinical trial going.
The Cochrans and the Dashiells continue to fundraise and are thrilled with the progress that’s been made since they started their organization.
Declan is now 5 years old and in kindergarten. Cochran says he is fully verbal, which is the greatest blessing, and he is starting to read but struggles with fine and gross motor skills. He uses a walker in school because he can’t stand on his own yet.
“He gets frustrated that his balance is not good,” says Cochran. “And when he falls down, he gets angry and upset. That's what hurts my heart because he's aware of everything. He is smart and his brain and body just aren’t communicating like they should. My hope for him is to be able to take something to make his life easier, to make his brain process things more easily, and to increase his ability to live his life with more ease. He deserves every opportunity; all the children do."