Making neurons lose their inhibitions

CIRM grantees at Sanford-Burnham have just published an interesting paper in PLoS Biology about developing a type of neuron that could alleviate symptoms of Huntington's disease, autism, schizophrenia and bipolar disorder — all diseases in which some neurons lose their inhibitions.

First, the big picture. In the brain, some neurons send signals to other neurons, relaying information around the brain. Others simply act to dial up or down those signals. A group of neurons in a part of the brain called the basal ganglia serve to dial back signals from other parts of the brain, basically keeping the signals under control.

In some neurological diseases, it's the loss of those inhibitory neurons that allow signals to run rampant and cause symptoms. In which case, adding some new inhibitory neurons might be what it takes to control symptoms.

What postdoctoral fellow Christina Chatzi knew is that some inhibitory neurons rely on a molecule called retinoic acid in order to develop properly. Retinoic acid is a form of vitamin A that has long been known to aid in developing limbs and body patterning. Working in the lab of Gregg Duester, Chatzi wondered if exposing embryonic stem cells to retinoic acid could result in these inhibitory neurons. Turns out she was right.

Duester's lab studies the basic biology of the role of retinoic acid in development, but they say others may want to follow up on this work in attempt to develop therapies. Sanford-Burnham's excellent blog entry quotes Duester:

"But what we found here suggests that others could use retinoic acid to make inhibitory neurons to treat disease, just the way an embryo does it naturally."

This work is one great example of how basic biology can feed into the development of new therapies -- something we've blogged about before. Without a constant source of new ideas going into the research pipeline there will be no cures coming out the other end.

CIRM funds two awards to scientists working toward therapies involving inhibitory neurons derived from embryonic stem cells: A comprehensive award to Arnold Kriegstein at the University of California San Francisco, and an Early Translational II award to Arturo Alvarez-Buylla also at UCSF.

- A.A.

CIRM funding: Gregg Duester (RS1-00193)
PLoS Biology, April 12, 2011

iPS cells lead to drug discovery for heart disease, autism up next

We’ve long claimed that one ideal role for iPS cells is modeling disease and screening drugs. In fact, we’re so committed to that idea we produced a video about it with CIRM grantee Bruce Conklin at the Gladstone Institutes. Scientific American also has a story on disease model their March issue, available online.

Well, a group at Stanford has proven us right. A team led by Ricardo Dolmetsch took skin cells from people with a heart condition called long QT syndrome, reprogrammed those to an embryonic-like state, then matured them into heart muscle cells. These heart cells contracted in the lab dish, but slower and with irregularities compared to similar cells created from people without the heart condition. The work was published online Feb. 9 in Nature.

Here’s the cool part. The team bathed those cells in a variety of different drugs that have been reported to affect heartbeat rhythms, and found one that restored a regular heartbeat in the diseased cells. The drug, called roscovitine, is currently in clinical trials for a different condition.

According to a Stanford University press release:

Dolmetsch cautioned that at this point roscovitine should not be considered an adequate treatment for LQTS — it hasn’t been tested for this purpose in living animals, let alone humans, and may have pronounced side effects. Still, he said, it’s a promising compound for further drug development. Stanford’s Office of Technology Licensing has applied for U.S. patents related to the discovery, and Dolmetsch is starting a new company that intends to license those patents once they’re granted.

The primary focus of Dolmetsch’s work is autism. The cells he created with irregular heartbeat came from people with a condition called Timothy syndrome, which causes long QT syndrome as well as a form of autism. He has a CIRM Tools and Technologies II award to create iPS cells from people with Timothy syndrome, mature those into neurons and test drugs to find one that improves signs of autism in those cells.

- A.A.

Stem cell model of autism allows testing of new drugs

Back in May 2009, CIRM held a workshop in which leading scientists discussed ways in which stem cell research could benefit people with autism (here is the autism workshop report from that meeting). I have two friends with children who are on the spectrum and have seen first-hand the toll the disease takes on the families.

This week, some CIRM grantees published an exciting paper that reflects the hopes of that workshop. The scientists took skin cells from people with a severe form of autism called Rhett syndrome, reverted those cells to an embryonic state, and matured them into neurons. The work was published in the in the November 11 issue of Cell. This is the first time scientists have been able to study what amount to autistic neurons in a lab dish.

It turns out they have some abnormalities, as you might expect. According to Technology Review:

They found that neurons derived from patients with Rett syndrome showed certain abnormalities, including markedly smaller cell bodies, dendrite connections, and decreased cell-to-cell communication.

The best part is that when the team from the Salk Institute and the University of California, San Diego exposed these neurons to a protein called insulin-like growth factor the neurons looked more normal.

This type of work is precisely what the workshop recommended as a starting point. Nerves grown from people with autism are an ideal environment for testing possible therapies and for understanding the disease. The group hopes to test therapeutic options suggested by these findings in mice, and to grow neurons from people with different forms of autism.

At this point the work is far too early to benefit my friends. The scientists still need to better understand the different forms of autism, study this proposed therapy in animals and understand the mechanism better before they can even begin thinking about a human trial. But for a disease that currently has so little clinical hope, even early stage work is a step in the right direction.

CIRM funding:
Fred Gage (RL1-00649-1 and RC1-00115-1)