Genome Center scientists awarded grant for rare genetic disorder research

The state stem cell agency, the California Institute for Regenerative Medicine (CIRM), today approved a $1.1 million grant to UC Davis for research aimed at developing a treatment for Angelman syndrome, a rare, neurogenetic autism-spectrum disorder that occurs in one in 15,000 live births.

Because Angelman syndrome is caused by a maternal gene that is turned off in the child, the UC Davis research team led by David Segal, professor of biochemistry and molecular medicine, and Jan Nolta, professor and director of the university’s stem cell program, plans to use mesenchymal stem cells (MSCs) as a delivery vehicle for a gene-modifying protein that recognizes and binds to the specific gene sequence that causes Angelman and turns the gene “on” using artificial transcription factors.

CIRM reviewers noted that while the disease is rare, the methodology proposed by the Davis team could be adapted to address other more common and complex brain disorders such as Huntington’s disease, CDKL5-deficiency, ALS and, potentially, some forms of genetically-linked epilepsy.

“Almost every disease has a genetic component,” said Segal, who has been investigating the rare neurogenetic disease for six years and is affiliated with the UC Davis Genome Center. “Often that information is used only to determine how a disease might progress in an individual. Thanks to this CIRM grant, we hope to develop an approach using genetic information that actually could fix a disease.”

Angelman syndrome is a devastating condition that requires life-long care and for which there are currently no medical treatments. It is characterized by developmental delays, lack of speech, seizures, and walking and balance disorders. According to the Foundation for Angelman Syndrome Therapeutics, individuals are often initially misdiagnosed as having cerebral palsy or an autism spectrum disorder.

Because of its genetic relationship to autism and other disorders, researchers believe that finding a way to treat the disease will lead to cures for similar disorders.

The research team, which includes Peter Deng, Kyle Fink (UC Davis Institute for Regenerative Cures) and Jill Silverman (UC Davis MIND Institute), will use MSCs to deliver an artificial transcription factor (a type of protein that can target and modulate genes) to neurons in the brain. The protein-based approach has already seen success in the animal model of the disease, but is not feasible for translational research.

The UC Davis approach depends on the ability of the MSCs to enter the brain, cross the blood-brain barrier, and secrete enough of the protein to reactivate the silenced gene (known as “Ube3a”) and provide functional recovery without causing inflammation.

“Our goals are ambitious but vital for giving hope to patients and families in need,” said Nolta, who also directs the UC Davis Institute for Regenerative Cures in Sacramento. “The need for effective treatments cannot be understated. Molecular therapeutics that help us better understand and treat single-gene disorders like Angelman will also enable us to also develop clinical tools for other disorders. ”

Today’s grant is part of the stem cell agency’s Discovery Quest program, designed to promote the discovery of promising new stem cell-based technologies that could be translated for broad use and ultimately improve patient care. Quest projects are aimed at “technology that is uniquely enabled by human stem/progenitor cells.”

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