UCSF scientists receive grants to refine embryonic stem cell-based strategies for neurological diseases

UCSF scientists have received two grants from the California Institute for Regenerative Medicine to refine their human embryonic stem cell-based strategies for treating neurological diseases and liver failure. The goal of the grants is for researchers to make significant strides toward the development of potential therapies within the next three years.

If the strategies prove successful, they could then be further prepared as potential therapies and submitted as new drug applications to the U.S. Food and Drug Administration, leading toward clinical trials.

One team, led by Arturo Alvarez-Buylla, PhD, UCSF Heather and Melanie Muss One team, received a $1,752,058 grant to further investigate their novel strategy using embryonic neurons to inhibit the hyperactivity that occurs in the nervous system in several neurological conditions. Maintaining the balance between inhibitory and excitatory signaling in the nervous system is critical to normal neurological function.

The research supported by the grant will focus on epilepsy, but potentially could be used to treat Parkinson's disease, traumatic brain injury, and spasticity after spinal cord injury.

"In 20 to 30 percent of patients with epilepsy, seizures are unresponsive to drugs, requiring invasive surgical resection of brain regions with aberrant activity," says Alvarez-Buylla.

"The candidate cells we propose to develop can inhibit hyperactive neural circuits after implantation into the damaged brain. These cells have the unique ability to disperse through the adult brain and become functionally integrated in the neural circuitry. By bringing back a balance between excitation and inhibition in the nervous system, these cells could have important therapeutic benefits."

Another team, led by Mark Zern, MD, of University of California, Davis, includes UCSF co-principle investigator Holger Willenbring, MD. The scientists will use their $5,199,767 grant to develop therapeutically effective liver cells, or hepatocytes, from human embryonic stem cells.

"Previous studies have shown that human embryonic stem cell-derived hepatocytes can provide liver function in rodents," says Willenbring. "We will be seeking to produce human liver cells that stand the test of curing a mouse model of human liver failure, with an eye toward clinical application."

"The cells could be used in patients suffering acute liver failure and those requiring such large liver resections that the residual hepatocyte mass wouldn't be able to provide enough liver function until natural regeneration had occurred."

The projects are among the 19 "translational research" awards announced yesterday by CIRM. The projects are expected to either result in a proposed drug or cell therapy or lead to significant progress in the development of a potential therapy, which could then be further developed for submission to the FDA for clinical trial.

The strategy being developed by Alvarez-Buylla, Scott Baraban, PhD, professor of neurological surgery, Arnold Kriegstein, MD, PhD, professor of neurology and director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell research at UCSF, and John Rubenstein, MD, PhD, professor of psychiatry, involves a set of embryonic cells known as medial ganglia eminence (MGE) neurons. These cells mature into so-called GABAergic inhibitory interneurons, which play a key role in maintaining the balance between inhibitory and excitatory signaling in the nervous system.

In previous studies, the team determined that when the embryonic neurons are transplanted into the brains of mice they mature, integrate into neural circuitry and reduce the overactive excitatory signaling that occurs in some neurological diseases.

In mice genetically engineered to have a human form of epilepsy, for instance, the cells decreased the number and severity of seizures. (Proceedings of the National Academy of Sciences, vol. 106, no. 36, 2009) . In mice genetically engineered to have an illness resembling Parkinson's disease, the cells improved balance, speed, and length of stride during walking. In healthy "control" rats in which the cells had been transplanted, the animals took longer strides and ran faster on a runway test (Cell Stem Cell (vol. 6, issue 3, 2010),

In the current study, the team will examine at a detailed level what happens to the MGE cells when they are grafted into the mouse brain. They will examine whether the cells mature appropriately and migrate to the intended locations in the brain, how they interact with the native neurons, how many are required to increase inhibition (dose-response information) and whether they have unwanted side-effects.

While the team previously used MGE neurons from the brains of embryonic mice, in the current study they primarily will use human MGE neurons they produced in the culture dish from human embryonic stem cells - work that was funded by a CIRM "Comprehensive" grant to Kriegstein in 2007. The human MGE neurons will be compared to mouse MGE neurons, which remain the "gold standard" for the research.

UCD's Zern and UCSF's Willenbring will work to develop high quality human liver cells, or hepatocytes, from human embryonic stem cells in the culture dish. They will test the effectiveness and safety of these cells and thus their potential for regenerating human liver in a mouse model of fatal liver disease.

Willenbring previously has shown that hepatocytes derived from reprogrammed skin cells -- a type of pluripotent stem cell similar to embryonic stem cells -- are in principle capable of curing liver failure in mice. Over the last seven years, Zern has developed protocols for the differentiation of human embryonic stem cells into hepatocytes. "The hepatocytes we are producing provide levels of liver function that are on average within 10-20 percent of that of primary human hepatocytes," says Willenbring.

Now, the team will refine the process by further maturing the hepatocytes, and develop strategies for "purifying," or selecting, the cells in the culture dish to make sure that only fully differentiated, or specialized, liver cells are transplanted.

"We have really promising preliminary results. Now we have to put the strategy to the test and develop it further in animal models, with the ultimate goal of rescuing liver function in patients who would otherwise die of liver failure."

The new awards brings the total funds awarded to UCSF by CIRM to $110,532,518.