FAST Grant Awarded for Potential Disease-modifying Syn Compound
Funding will be used to study novel therapeutic CN2097 in Angelman
The Foundation for Angelman Syndrome Therapeutics (FAST) has awarded a research grant to a project testing a new type of therapeutics — a potential disease-modifying compound called Syn — for Angelman syndrome.
According to a FAST press release, the grant was awarded to John Marshall, PhD, a professor of medical science at Brown University in Rhode Island.
“The results of this project will be used to inform a potential novel treatment option for humans living with Angelman syndrome,” the foundation stated.
Preliminary studies have shown that Syn compounds can improve learning and restore normal mobility in a mouse model of the genetic disorder.
Investigating the Syn compound in Angelman
Angelman syndrome is a rare neurological disorder caused by the absence or malfunction of the UBE3A gene in the brain. This leads to symptoms that include developmental delays, animated behavior, coordination issues, and limited speech capabilities.
Scientists have developed an animal model of the disease by creating mice that do not have the UBE3A gene in the brain. These mice have symptoms that resemble those of the human disease, such as motor dysfunction, seizures, and impaired learning.
Research in this mouse model revealed that the lack of the UBE3A gene disrupts the normal processes of long term potentiation (LTP), a neuronal mechanism that is widely believed to be crucial for learning.
In prior research, Marshall and his colleagues connected this disrupted LTP mechanism to the impaired activity of brain-derived neurotrophic factor, known as BDNF. That signaling protein regulates several processes in the brain, including those crucial for learning and memory consolidation.
“We started studying BDNF signaling in the Angelman syndrome mouse and discovered the signaling was defective, so that really was the breakthrough,” Marshall said in a Brown University press release in 2013 that reported on that research.
The team of scientists went on to test a novel synthetic compound called CN2097. This compound was able to reinstate BDNF signaling and LTP, thereby improving neuronal function in the Angelman mouse model.
One issue with CN2097 is that it degrades within hours, potentially leading to frequent dosing to sustain its effects.
More recently, Marshall’s group has been working on two goals. The first was to further study CN2097 and its potential benefits in learning and motor function. Secondly, the scientists are using their accumulated knowledge to develop new compounds that mimic CN2097’s action but with a longer period of activity.
Among these new molecules is the compound Syn — the focus of the FAST grant now awarded to Marshall.
The funded project is exploring Syn compounds in the Angelman syndrome mouse model, with the goal to uncover promising candidate therapies for the disease.
“This study will support numerous Syn compounds to undergo further animal studies to determine which has the best safety profile and the ability to treat the symptoms (learning and walking/gait/coordination) in the [Angelman syndrome] animal models,” FAST stated in the release.
Marshall spoke on his work to date at FAST’s recent Translational Research Symposium.