FAST Awards $500K to Research of Less-invasive Brain-directed Therapy

Two-year grant awarded to Barbara Bailus, PhD, at Keck Graduate Institute

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by Patricia Inacio, PhD |

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The Foundation for Angelman Syndrome Therapeutics (FAST) has awarded a $500,000 grant to support the development of a less-invasive, brain-directed therapy for people with Angelman syndrome.

The two-year grant was awarded to Barbara Bailus, PhD, an assistant professor of genetics at Keck Graduate Institute, in California. Her winning project is titled “Targeting Angelman Syndrome Therapeutics to the Brain Utilizing Novel Cell-Penetrating Peptides.”

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Angelman syndrome is a rare neurological disorder characterized by developmental delays, characteristic facial features, seizures, sleep problems, and frequent laughing. It is caused by the loss or malfunction of the maternal copy of the UBE3A gene, which provides instructions to produce a protein of the same name.

Since the maternally inherited copy of UBE3A is the only active copy in specific regions of the brain, mutations or the complete loss of this copy result in UBE3A deficiency in nerve cells and the neurodevelopmental symptoms seen in patients.

Currently, no specific treatment exists for Angelman, and available therapies can only help manage symptoms. Previous research suggests that replacing the faulty maternal UBE3A copy or promoting the activation of the paternal copy in nerve cells could hold therapeutic potential.

However, in most of these potential approaches, “you must directly inject the drug into the brain, or fluid surrounding the brain,” Bailus said in a university press release. “The trick here was to find a way around that.”

During her PhD in the lab of David Segal, PhD, a professor at University of California, Davis, Bailus set out to develop a less invasive way of re-activating the silent paternal UBE3A copy in brain cells.

Team designs molecule that could cross the blood-brain barrier

The team designed a lab-made transcription factor — a molecule that can regulate the activity of specific genes — that could cross the blood-brain barrier and reach the brain. This barrier is a highly selective membrane that tightly regulates what substances from the bloodstream can access the brain and spinal cord.

The researchers found that when delivered directly under the skin or into the abdominal cavity, this transcription factor effectively increased UBE3A levels in the brain of a mouse model of Angelman syndrome.

The trick here was that the researchers “added a cell-penetrating peptide to the protein, which is essentially a backstage pass to the brain, carrying the protein across the blood-brain barrier and into the neurons of the brain,” Bailus said.

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Now, with the new grant, Bailus and her team plan to test up to three novel cell-penetrating peptides and their ability to carry their therapeutic targets in human cells and mice brains.

“This is a very exciting project that could change the landscape of drug delivery for neurologic disorders,” said Allyson Berent, FAST’s chief science officer. “There are many companies and stakeholders that are very much looking forward to the results of this study, and we are thrilled that the disease model being utilized to test these novel constructs is Angelman syndrome.”

Bailus added: “it’s such an honor to work with the Angelman syndrome community and with an organization that’s been able to focus on actually moving into clinical trials and impacting humans living with this rare disease.”

“I am beyond excited to get started on the research.”