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Families of children with rare diseases will often start non-profit organizations to raise money for early-stage research on their child's condition.

Fewer of those organizations start their own biotech company to drive drug development -- but that was the case for the Foundation for Angelman Syndrome Therapeutics, or , a rare disease group whose entire board is made up of parents whose children have Angelman syndrome, a rare neurodevelopmental disorder.

A few years ago, FAST created a biotech company called GeneTx to push forward the development of an antisense oligonucleotide (ASO) drug for Angelman syndrome. Last summer, the organization plus future milestone and royalty payments.

"Now we have additional money to pour back into the pipeline," Alana Newhouse, president of FAST and the mother of a child with Angelman syndrome, told 番茄社区app.

Angelman syndrome occurs in about one in 20,000 births, so it's not likely that any other biotech might have taken such a risk on an early-stage compound, especially given the likely low return-on-investment. But in 2016, FAST members' business savvy, combined with their dedication to their children, laid the foundation that enabled it to invest in such development.

What Is Angelman?

Angelman syndrome is a neurodevelopmental disorder caused by mutations or a deletion in the maternal copy of the UBE3A gene, which expresses a protein by the same name. One of the main functions of UBE3A is to target other proteins for degradation.

UBE3A is ubiquitous throughout the body, and both maternal and paternal copies can be expressed anywhere except in the brain -- where paternal UBE3A is always suppressed. Thus, if maternal UBE3A is faulty, the protein won't be expressed and proteins will start building up in the brain.

"If you're missing it, you have accumulation of proteins within the brain, and there are a lot of ways that can affect how the brain functions and communicates synapse to synapse," said Nycole Copping, PhD, science director at FAST.

Joseph D'Orazio, MD, an emergency physician in Philadelphia, serves on an advisory board at FAST. was diagnosed with Angelman syndrome in 2018, and he noted that is on Wednesday, February 15 this year.

"He's a very happy kid," D'Orazio told 番茄社区app. "He's laughing all the time. He'll laugh at really benign things. People who don't know him are like, 'Oh, he's a really happy kid.' But that laugh is actually just a response to everything. When he's nervous he laughs. When he's scared he laughs. When he's stressed out he laughs. When he's happy he laughs, too, so it's just a very pleasant demeanor."

Turning Point

FAST's unique approach to pushing forward drug development in Angelman syndrome started in earnest in 2016, when the organization secured a nearly $6 million philanthropic grant from the Marnier-Lapostolle Foundation, which was founded by the family that invented Grand Marnier liqueur. The philanthropy was inspired by a family member who had Angelman syndrome, Newhouse said.

Allyson Berent-Weisse, whose daughter has Angelman syndrome, had joined FAST in 2015 as its chief science officer. Berent-Weisse revamped the organization's research roadmap, focusing on six pathways that would be the most promising in terms of leading to a treatment for the disease. She estimated the development of all six would cost $5.8 million, and the philanthropy funded the entire venture.

One of those strategies was the ASO, named GTX-102. FAST secured a license for the compound and launched GeneTx, its first company, around it.

Newhouse noted that Ultragenyx initially took an interest in the compound when it looked like it would move into human clinical trials, making an investment of several million dollars to push it through an early study.

With that investment, Ultragenyx was granted an option to acquire the company, , Newhouse said.

At that time, data were available on 11 patients from the phase I/II trial. In a of both interim clinical trial data and the acquisition, Ultragenyx said the compound showed acceptable safety and early signs of improvement of clinical disease.

The trial did have a setback in 2020, when the FDA placed a clinical hold on it after some patients developed limb weakness. The side effect was ultimately tied to inflammation at the infusion site -- GTX-102 is delivered via intrathecal infusion -- and the trial was eventually .

ASO candidates appear to hold the most promise as a treatment for Angelman. There are two others in development aside from GTX-102: one from , and another from .

Since the paternal copy of the UBE3A gene exists but is just silenced, the goal of the ASO technology is to unsilence paternal UBE3A in order to ramp up protein production. It does so by attaching to the antisense transcript that silences paternal UBE3A, preventing the silencing of the gene, Copping said.

Backing Other Strategies

FAST is still focused on those five other treatment strategies that it had bet on with its initial large philanthropic grant. The group has added four other strategies since then, according to its website.

One of those strategies is gene therapy. It's not as far along as the development of ASO therapeutics, and the field of gene therapy has had its own setbacks over the past couple of decades.

Nonetheless, FAST has licensed a lentiviral gene therapy and formed a new company around it, .

"We're not in a position, currently, to take therapeutics all the way through a pipeline," Newhouse said. "That amount of money is beyond what we can do. What we try to do is guardrail therapeutics far enough and find the right partners along the way so we can protect and nurture a therapeutic that appears promising."

The organization's biotech savvy is matched by its drive to help its children: "In the rare disease community, it's harder than advocating for a disease that is more well known and affects more people," Newhouse said. "You need a louder voice."

"It's important for us to band together as a community of families struggling to create opportunities for our loved ones so that we can be heard and we can get our needs met," she added. "You are your kid's best hope."

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