Exploring a New Way to Combat Genetic Disease

By Troy Goodman

UAB cystic fibrosis researchers David Bedwell and Steven Rowe
David Bedwell, left, and Steven Rowe are part of a team of UAB researchers studying cutting-edge treatments for cystic fibrosis.

The period in this sentence is not in the. right place Chances are, that didn’t throw you off too much. Human beings are remarkably tolerant of textual trouble; our brains can wrestle meaning out of a sentence in the face of all manner of grammatical errors, spelling mistakes, and dropped words. When it comes to reading life’s little instruction book, however, our bodies are as inflexible as a computer program. One little mistake can literally make the difference between life and death.

Errors in the body’s underlying genetic code are at the root of a host of diseases, including cystic fibrosis, hemophilia, muscular dystrophy, sickle cell disease, and many types of cancer. Even though scientists have become very good at tracking down the offending sections of code that cause these conditions, they have been far less successful at finding a way to repair the damage. That’s why an experimental drug being tested in the lab of UAB microbiologist David Bedwell, Ph.D., takes a different approach to tackle one devastating subset of genetic errors. It induces the body to skip over those errors—restoring enough function to make a big difference in patients’ lives.

Full Stop

Each cell in your body contains an instruction book—a blueprint that tells that cell how to build the proteins and other bits of biological machinery it needs to fulfill its duties. The blueprint is DNA, and it is subdivided into a series of specific building plans called genes. Because these instructions run in a continuous sequence with billions of individual entries, the system relies on special “start” and “stop” signals to indicate when the instructions for one gene end and the next begins.

When an error—that is, a mutation—works its way into these instructions, the process goes awry. Mutations come in a wide variety of forms, from multiple sources (including viruses, the sun’s rays, and errors in cell division) and with consequences ranging from the benign to the catastrophic.

When a stop signal mistakenly appears inside a gene, preventing it from transmitting its complete set of instructions, this is called a “nonsense” mutation. The result is incomplete, and often useless, proteins. Depending on the importance of the protein, there also can be a cascade of downstream effects.

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Ataluren illustration courtesy PTC Therapeutics
The body's genetic production line relies on stop signals (codons) to tell it where each protein begins and ends. Nonsense mutations disrupt the system by inserting these stop codons in the wrong places, leading to incomplete proteins and a host of problems—including roughly one-third of inherited diseases. Investigators at UAB are testing an experimental drug called ataluren that tackles the problem by skipping over the incorrect stop codons. Image courtesy PTC Therapeutics

Roughly one-third of inherited diseases are caused by nonsense mutations. For example, cystic fibrosis (CF) occurs when nonsense mutations affect the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR helps to regulate fluid production in the body; when it malfunctions, thick layers of mucus build up in the lungs and digestive tract, causing fatal lung infections and digestive problems.

The ideal solution to the nonsense problem would be to eliminate the misplaced stop signals and restore the DNA message to its natural state. So far, this has proved impossible. Instead, UAB’s Bedwell and colleagues have spent several years testing an alternative in the form of an experimental compound called ataluren. The drug, which is manufactured by PTC Therapeutics, works by binding to a part of the cell called the ribosome and inducing it to ignore faulty genetic stop signs, thereby restoring gene function.

Playing the Numbers

Skipping over the problem rather than dealing with it directly seems to be a less-than-ideal solution, but perfection isn’t necessary, explains Bedwell, a leading CF researcher and member of UAB’s Gregory Fleming James Cystic Fibrosis Research Center. “It comes down to a numbers game,” he says. “When you treat a genetic disease, the bottom line is how much of the missing protein do you need to restore to have a therapeutic benefit?”

More Ways to Fight CF
UAB's Steven Rowe is studying another new approach to cystic fibrosis treatment: an investigational drug called VX-770 that also targets the faulty gene at the root of the disease.

In one high-profile study using animal models of cystic fibrosis, Bedwell’s lab reported that ataluren restored up to 29 percent of normal CFTR function. Another researcher not affiliated with UAB has reported that ataluren restores up to 25 percent of the missing or abnormal protein function in animal models of Duchenne muscular dystrophy.

The drugs don’t have to achieve complete restoration to bring about major improvements in patient function, notes UAB assistant professor of medicine Steven Rowe, M.D., who works with Bedwell and other investigators on leading-edge CF treatments. “Some CF patients have mild forms of the disease,” Rowe says. “For example, you can have two bad proteins, one of which is completely bad and one of which is partially functional, and that’s enough to give you a mild form of the disease.”

A 5 or 10 percent improvement in protein activity would be “enough to change a severe case into a mild form of CF,” Rowe continues. “And if we can achieve a 20 or 30 percent improvement in protein activity, we have come a long way towards a cure in those patients.”

Many Possibilities

The beauty of drugs like ataluren is that they could be useful with many diseases that result from nonsense mutations, says Rowe. PTC Therapeutics is now testing ataluren in humans for its effectiveness in hemophilia A, hemophilia B, and other conditions.

Some diseases caused by nonsense mutations—such as the enzyme disorder known as Hurler syndrome—are even more sensitive to improvements in protein function than CF. Hurler patients usually die within their first decade after experiencing progressively worsening symptoms, including skeletal deformities, hearing loss, heart failure, and mental retardation. UAB’s Kim Keeling, Ph.D., and her colleagues in the Department of Microbiology are studying the underpinnings of the disease—and potential treatments, such as ataluren—in animal models.

Bedwell and other UAB investigators began their nonsense-mutation work at the most basic level, studying one-celled organisms. Now they’ve taken the concepts all the way to human clinical trials, and they are eager to see their hard-won knowledge translated into a patient-ready therapy. UAB is part of a large, multicenter study that is testing the effectiveness of ataluren as a CF treatment.

“This work is really about collaboration and years of breakthroughs from many UAB investigators,” says Bedwell. “We’re treating patients on a one-year trial to see if they get the health benefits and symptom control we hope for.”


More Information

UAB Gregory Fleming James Cystic Fibrosis Research Center