UCLA stem cell researchers move toward treatment for rare genetic nerve disease

Led by Dr. Peiyee Lee and Dr. Richard Gatti, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have used induced pluripotent stem (iPS) cells to advance disease-in-a-dish modeling of a rare genetic disorder, ataxia telangiectasia (A-T).

Their discovery shows the positive effects of drugs that may lead to effective new treatments for the neurodegenerative disease. iPS cells are made from patients' skin cells, rather than from embryos, and they can become any type of cells, including brain cells, in the laboratory. The study appears online ahead of print in the journal Nature Communications.

People with A-T begin life with neurological deficits that become devastating through progressive loss of function in a part of the brain called the cerebellum, which leads to severe difficulty with movement and coordination. A-T patients also suffer frequent infections due to their weakened immune systems and have an increased risk for cancer. The disease is caused by lost function in a gene, ATM, that normally repairs damaged DNA in the cells and preserves normal function.

Developing a human neural cell model to understand A-T's neurodegenerative process - and create a platform for testing new treatments — was critical because the disease presents differently in humans and laboratory animals. Scientists commonly use mouse models to study A-T, but mice with the disease do not experience the more debilitating effects that humans do. In mice with A-T, the cerebellum appears normal and they do not exhibit the obvious degeneration seen in the human brain.

Lee and colleagues used iPS cell–derived neural cells developed from skin cells of A-T patients with a specific type of genetic mutation to create a disease-in-a-dish model. In the laboratory, researchers were able to model the characteristics of A-T, such as the cell's lack of ATM protein and its inability to repair DNA damage. The model also allowed the researchers to identify potential new therapeutic drugs, called small molecule read-through (SMRT) compounds, that increase ATM protein activity and improve the model cells' ability to repair damaged DNA.

"A-T patients with no ATM activity have severe disease but patients with some ATM activity do much better," Lee said. "This makes our discovery promising, because even a small increase in the ATM activity induced by the SMRT drug can potentially translate to positive effects for patients, slowing disease progression and hopefully improving their quality of life."

What is ataxia-telangiectasia?

Ataxia-telangiectasia is a rare inherited disorder that affects the nervous system, immune system, and other body systems. This disorder is characterized by progressive difficulty with coordinating movements (ataxia) beginning in early childhood, usually before age 5. Affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The movement problems typically cause people to require wheelchair assistance by adolescence. People with this disorder also have slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia). Small clusters of enlarged blood vessels called telangiectases, which occur in the eyes and on the surface of the skin, are also characteristic of this condition.