UCLA scientists have devised a novel way to repair one of the genetic mutations that causes ataxia-telangiectasia, (A-T), a life-shortening disorder that devastates the neurological and immune systems of one in 40,000 young children.
Reported Oct. 18 in the Proceedings of the National Academy of Sciences, the findings could hold far-reaching implications for treating A-T, cancer and other genetic diseases.
Often misdiagnosed as cerebral palsy, A-T usually strikes children before age 2 and confines them to a wheelchair by age 10. Many lose their ability to speak, and die in childhood. One in three of these children also develop lymphoma or leukemia. Adults who carry the mutated A-T gene (ATM), including up to 15 percent of breast-cancer patients, are eight times more likely to develop cancer than the general population.
Dr. Richard Gatti, professor of pathology and laboratory medicine, and Chih-Hung Lai, a postdoctoral researcher at the David Geffen School of Medicine at UCLA, created a new strategy for tricking the ATM gene into overlooking certain types of mutations called premature termination codons (PTCs).
"PTCs are like irregular stop signs located in the middle of the block," Gatti said. "They stop traffic before it reaches the intersection. We made these stop signs invisible, so traffic continues until it sees the proper stop sign at the end of the corner."
In normal cells, termination codons alert the cell's protein-reading machinery that a protein has reached full length and completed copying. In the mutated genes of A-T patients, PTCs halt the copying of proteins too early, resulting in shortened and unstable ATM proteins.
"Unstable proteins create abnormal cells that can't function properly, producing all of the neurological and immune problems that afflict A-T patients," said Lai, the study's first author.
Lai and Gatti noted that A-T patients whose cells contain no ATM protein suffer from a severe form of the disease, while patients whose cells hold some ATM protein have a milder form of the disorder. The scientists hypothesized that increasing ATM protein in the cells, even by modest amounts, might alleviate A-T patients' symptoms or perhaps eliminate the disease entirely.
The team used a group of antibiotics called aminoglycosides to make the PTCs invisible to the cell's protein-reading machinery. After bathing in the antibiotics for four days, cells that earlier contained little or no ATM proteins had grown full-length ATM proteins.
When the researchers tested the treated A-T cells, they also discovered that the cells had converted to normal appearance and begun to function normally. The cells started churning out ATM protein, which provides energy by switching on other cells.
"About one in six A-T patients has a PTC type of mutation," Lai said. "We hope that our findings will provide a solid first step to gene-based therapy for this group."
According to Gatti, many aminoglycosides are already approved for clinical use by the FDA and could quickly become available for testing in A-T clinical trials.
"Our next step will be to build an ATM animal model and see how it responds to aminoglycoside therapy," Gatti said. "We will also screen other antibiotics and drugs that may restore ATM cell function even better. We only need one successful candidate to make a huge difference in the lives of children with A-T."
Because the ATM gene also increases cancer risk, Gatti is hopeful that his laboratory findings may hold implications for cancer diagnosis and treatment.
"If we are able to restore A-T cell function, we may be able to halt the spread of the tumor," Gatti said. "By correcting the mutation, the cancer may stop growing or recede entirely."
Everyone carries two copies of the A-T gene, but one copy is defective in A-T carriers. Children who inherit a defective gene from each parent will develop the disease. Gatti's laboratory was the first to locate the ATM on chromosome 11 and then worked to clone it successfully.
The National Institute for Neurological Disorders and Stroke and the A-T Medical Research Foundation funded the study.