Antisense Therapies and Angelman Syndrome
Lauren Black

Antisense Therapies and Angelman Syndrome

The chances of finding a cure for Angelman Syndrome, a rare genetic disorder are looking better and better

In 1964, English pediatrician Harry Angelman treated three children who shared very unusual qualities: happy disposition, love of water, lack of speech, small stature, incoordination, and seizures. His findings appeared in Developmental Medicine and Child Neurology a year later, describing what came to be known as Angelman Syndrome (AS).  He was able to describe the syndrome, but didn’t know what triggered it. We now we know that 1:20,000 children worldwide are affected with AS. They typically are long lived, but require continuous personal care which is very difficult for their families and caretakers to provide.

In the 1990s, scientists solved the puzzle of what causes AS. Using individual genome sequencing, they found AS was caused by losing one functional copy of a single gene that is normally carried on each of the two alleles in the patients’ cells – this gene is named UBE3A.   

To explain, genes are inherited as two copies, one from the mother and one from the father. Usually, the mother’s UBE3A gene is the active one, while, uniquely, for this specific gene, the father’s copy is silenced through a natural mechanism known as “imprinting”. It is nature’s way of fine-tuning this specific gene. 

In Angelman Syndrome, this fine-tuning backfires, because the mother’s copy is mutated or missing while the father’s copy is healthy but silenced by a swathing of RNA called the “antisense transcript”. Scientists have learned in the last several years that this “swathing” can be removed to reveal the healthy gene, which opens the door to gene modification therapy! 

The chances of finding a cure are looking better and better, thanks in large part to the ongoing financial support from foundations like FAST (Foundation for Angelman Syndrome Therapeutics), who are helping to drive both basic and translational research, as well as educating parents and loved ones about the condition and how to help provide the best possible life for those children affected.

Since 2011, FAST has invested more than US $14.7 million in research and hopes to raise an additional $6.7 million more by the end of next year. These funds support unique therapeutic programs as well as the FIRE Consortium, a unique collaboration model designed to encourage a multi-disciplinary team of scientists, who are in different universities, to work together in unison towards therapies for children and adults with AS. From these research initiatives, rare disease communities are learning about not only AS, but also other genetic drivers for autism, Alzheimer’s and Fragile X.

A Cure for Angelman Syndrome?

One of the most enticing drug strategies is oligo therapy. One of the FIRE collaborators, Dr. Scott Dindot at Texas A&M University, developed a potential therapeutic intervention for Angelman syndrome by removing the RNA swathing, using antisense oligonucleotides. Prior studies published in 2013 and 2015, performed in other laboratories, showed this proof-of- concept was plausible in both Angelman syndrome neurons  as well as in live rodents with an AS.

On the basis of this work, FAST launched a biotech company,  GeneTx Biotherapeutics, to help narrow the focus and drive this therapy through an IND-enabling study for patients with AS. The US Food and Drug Administration granted them orphan-drug designation last winter and hosted them for a patient advocacy meeting, both critical milestones in moving the therapy along more smoothly. GeneTx is also collaborating with many innovators, including Dr. Timothy Yu at Boston Children’s Hospital and experts at Charles River Laboratories, to accelerate the drug development program and arrange the clinical trial, hopefully next year.

A drug similar to this, called Spinraza, has dramatically helped children with another genetic disorder, spinal muscular atrophy, and its success and good safety record has helped pave the way for similar therapies to move forward more quickly. Simultaneously, the FDA is signaling a more proactive stance towards advanced medicines and rare diseases with clear readouts.

So there is clearly hope for finding therapies and perhaps even a cure for Angelman Syndrome.

"I am so honored to be a part of this incredible journey with our amazing development team, where we are able to bring forward a proof of concept in neurons to in vivo knockdown in large animal models, said Dr. Allyson Berent, the Chief Science Officer of FAST and the Chief Operating Officer of GeneTx Biotherapeutics. “Our team has been able to ensure this program is driven by experts in the field of antisense therapies, and we are moving forward in the safest and most methodical way. I am beyond excited to see a meaningful treatment being developed for children affected with Angelman syndrome. This is an amazing time for our community to be hopeful, and an even more amazing time for me as the mother of a child affected with this disorder." 

The Foundation for Angelman Syndrome Therapeutics is always interested in hearing from scientists with great ideas, and are continuing fundraising efforts to move forward this basic and accelerated treatment paradigm. Check out their website for further information – it is They are a wonderful example of foundations harnessing the power of both families and scientists to drive innovation. FAST will be hosting a summit and gala in Chicago Dec. 7 and 8 to raise money, share science and educate about Angelman’s.