Rare genetic disease ADNP Syndrome to be cured within 3 years

According to the ADNP Kids Research Foundation, only about 400 children in the world have been diagnosed with the syndrome. The very first child in the U.S. to receive the diagnosis was Tony Sermone.

ADNP syndrome is a complex neurodevelopmental condition caused by a mutation or change in the ADNP (Activity Dependent Neuroprotective Protein) gene, which affects brain development, connectivity and function. The syndrome, first identified in 2014, affects males and females in equal numbers.

Its core features include delays in development and growth, intellectual disability and autism or autistic characteristics. It is one of the top single-gene causes of autism.

The impacts of ADNP syndrome can be profound and may include delayed speech, low muscle tone and sensory processing challenges. The brain, heart and musculoskeletal system are often affected. ADNP syndrome is also associated with distinctive facial features, including a prominent forehead, eyes that are farther apart and droopy eyelids.

“It has been my goal since I started the foundation to find treatments for all individuals with ADNP syndrome as fast as possible, and this collaborative project is a big step forward, one we could never had made without the generosity of the Somaia family, to whom we are so grateful,” she said.

Through the foundation, Bedrosian Sermone connected with the Somaia family in Melbourne, Australia, where 2-year-old Tye was recently diagnosed with ADNP syndrome.

The program will include two major phases. First, the team will use stem cell technology to create a human ADNP model in Petri dishes. They’ll also characterize mice with ADNP mutations. That will involve looking at cognitive abilities, sleep changes, gait abnormalities and more. Finally, the team will do a deep molecular characterization of the cells in the mice.

“That information will be useful to anyone who wants to study ADNP,” Fink said. “We’ll be able to say, ‘in the mice at this age, there’s this big effect, so if you have a drug, you can test it in this mouse at this age using these tasks.’”

The second phase, the one that “everyone gets the most excited about,” noted Fink, is evaluating therapies for ADNP. To fast-track progress, the team will work simultaneously on three different therapies.

“We think of it as shots on goal,” Fink said. “Time is of the essence with these conditions.”

They’ll be evaluating a traditional gene therapy delivered using a virus - one that’s been used in clinical trials and approved by the FDA for spinal-muscular atrophy. The team will also assess an ASO (antisense oligonucleotide) that modulates gene expression by binding to mRNA. The third is being developed using the gene-editing tool CRISPR.

“When we use a form of deactivated CRISPR, we tell the cell how to regulate specific genes,” Fink explained.

The therapeutics get tested in mice, then in the cells, but rather than sequentially, they’ll be characterizing the mice and cells on parallel tracks. That will enable them to move much more quickly.

“We want to ensure we’re putting the resources into therapeutics that we really think will make a significant impact in more than just one domain of these kids’ lives. I think these three approaches really give us a great chance to find something that can move forward in a meaningful way,” Fink said.

A history of success

The team has had previous success with their work on another rare genetic condition, Angelman syndrome. Their labs helped create and characterize the first rat model of the syndrome. The Segal lab also developed a protein therapeutic that could increase the level of the affected gene in mouse models of Angelman syndrome – a major discovery.

The group is also working on a similar project to develop molecular therapies for the genetic condition SYNGAP1.

Additionally, Fink and Segal were part of a study that showed it was possible to reactivate a gene from the inactive X chromosome using epigenetic editing as a potential treatment for CDKL5 deficiency disorder, another rare neurodevelopmental condition.

“Jill, Dave and Kyle have a proven track record and are doing extraordinary work,” Abbeduto said. “This project is a perfect fit for them and the MIND Institute. There’s great synergy in the fact that this is being funded by families, just as the MIND Institute was founded by families with the same goal: improving life for children.”

Fink, Silverman and Segal are already recruiting new researchers in their labs that will be devoted to this project.

“We will train the next world leaders in ADNP research,” Fink said.

As the interventional genetics team builds on past success and fine-tunes its infrastructure for evaluating therapeutics, the researchers expect the work to reach far beyond ADNP.

That’s important to Bedrosian Sermone. “I’m a true believer that these rare diseases can be worked on at the same time. When you find something for one of us, you often find something for all of us.”

Tye’s mother, Zuzana Horakova, is also thrilled about the possible impact.

“I’m very hopeful and very positive about this project. If, in the future, we can open up the possibilities for all sorts of other rare diseases, too, that’s mind-blowing,” she said.