Friedreich's Ataxia Enters 'the Treatment Era'

by Dan Stimson

When Erin Kiernan was 7, a teacher noticed that her walking seemed a little off balance and mentioned it to Erin's parents.

"It was the way she would stand bent forward a little bit," says Erin's father, Pat. "We had noticed the same thing, but we kind of thought it was just us." With this confirmation that something might be wrong, they took Erin to the family pediatrician.

That visit sent the Kiernans on a 10-month journey of testing that ended with a diagnosis of Friedreich's ataxia (FA) — a genetic disease named for its discoverer (19th-century German physician Nikolaus Friedreich) and its progressive impairment of balance and coordination (ataxia). There's no cure, and Erin, now 13, is steadily losing her ability to walk and use her hands. More seriously, she's experienced some frightening cardiac problems — another common effect of FA.

But Pat and his wife, Karen, remain hopeful, because while Erin's FA has progressed, so has research on the disease. In 1996, scientists discovered that FA is caused by defects in a previously unknown gene, which they named frataxin, and since then, they've figured out that the frataxin protein helps regulate cellular iron stores and protect against oxidative stress — a buildup of oxygen-based free radicals.

This understanding of the mechanisms behind FA has pointed the way to drugs that might stave off its assault on the nervous system and heart. One of the most promising drugs, idebenone, is now being tested in a clinical trial at the National Institutes of Health (NIH) and, like many families with FA, the Kiernans are eager for the results.

About Erin

Since Erin's diagnosis, her FA has "progressed pretty significantly," Pat says.

Recently, she started using a walker to get around the Kiernans' home in Mt. Airy, Md., and a power wheelchair for going other places. It's getting hard for her to write, and her voice is showing signs of dysarthria — a slow, shaky pattern of speech caused by weakness and incoordination of the tongue and other facial muscles.

Erin, who was MDA's Maryland Goodwill Ambassador in 1999 and 2000, doesn't let these things get her down. She gets straight A's in school and has lots of friends, who enjoy occasional rides on the back of her wheelchair. "Even though I'm in a chair, I still have an active life," she says.

Still, her FA is turning simple, daily activities into real challenges.

"School is getting a little bit harder," she admits. "It's harder for me to get from class to class and from my seat to the hall. It's also getting hard to do my schoolwork." She's working with teachers and with speech, occupational and physical therapists to figure out ways to adjust to her FA.

And then there are the heart problems. They began about four years ago as nothing more than some abnormal results on an electrocardiogram (EKG) and other tests, but by late 2001 Erin was having symptoms.

"She was having a lot of trouble getting up and down the stairs, and she'd complain of chest pains from different exercises," Pat Kiernan says. "[Doctors] did a stress test by raising her heart rate with drugs … and she kind of hit a point where all of a sudden she was having a hard time."

Some medication and a stair lift helped get those symptoms under control, but since the underlying problems are still there, Erin has annual cardiac checkups.

About FA

Erin's progression has been unusually fast (most people with the disease can still walk for 10 to 15 years after its onset). But with regard to basic symptoms, her experience with FA has been fairly typical.

FA affects the heart and parts of the nervous system involved in muscle control and coordination. It's caused by inheritable defects in frataxin, a protein found inside cellular energy factories called mitochondria. Current research suggests that frataxin forms a storage depot for iron, which is essential in mitochondria but can cause damage if left unchecked.

The disease damages the spinal cord, the peripheral nerves that connect the spinal cord to muscles and sensory organs, and the cerebellum — a brain structure that helps coordinate movement (see illustration). The parts of the brain involved in thinking and conscious planning of movement aren't affected by FA. It's the erosion of muscle control, simple reflexes and the sense of the body's position in space that cause ataxia.

FA's effects on the heart tend to occur later in the disease, if at all. Common symptoms include chest pain, shortness of breath and palpitations. But the severity of heart problems varies widely from person to person, says David Lynch, an MDA grantee and neurologist at the University of Pennsylvania in Philadelphia.

"Probably greater than 75 percent of patients [with FA] have at least some cardiac abnormality — an abnormal EKG at minimum, severe life-threatening disease at worst," he says. "When we detect more than simply EKG changes, the basis is usually hypertrophic cardiomyopathy" — an enlargement of the heart's muscular walls that shrinks its inner chambers and decreases its pumping capacity.

Enlargement of the heart can lead to arrhythmia (a heartbeat that's too fast or too slow) and, in severe cases, to heart failure. For many FA patients, these problems can be controlled with treatments developed for cardiac disease in the general population. For example, a pacemaker may stabilize the heartbeat, and certain drugs (ACE inhibitors, diuretics, beta blockers) can decrease the heart's workload. But for some patients, these treatments aren't effective, Lynch says.

The FA Gene

Fortunately, idebenone and perhaps other drugs could be powerful treatments against FA — an idea that emerged, in part, from basic research on frataxin.

Frataxin was identified in 1996 (the same year as Erin's diagnosis) by MDA-funded researchers Michel Koenig of the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France, and Massimo Pandolfo, then at Baylor College of Medicine in Houston. Since it was unlike any other known protein, the researchers didn't have a clue about its function or how it might be involved in FA. In fact, other researchers proposed that the frataxin protein didn't even exist and that a different gene close to the reputed frataxin gene was actually the culprit behind FA.

(For more on FA genetics, see "Center Promotes Understanding.")

But Pandolfo and Koenig were able to identify the frataxin protein in humans and show that FA-causing mutations lead to a deficiency of frataxin. They also found

Grazia Isaya

Remarkably, it was research on a single-celled organism — baker's yeast — that pointed to frataxin's roles in iron regulation and oxidative stress.

"If you knock out the frataxin gene in yeast, you have a cell that's still viable, but it accumulates a huge amount of iron and loses its capacity for [energy production] due to mitochondrial damage," says Grazia Isaya, a leader in frataxin research at the Mayo Clinic in Rochester, Minn.

Iron is essential for energy production and is transported into mitochondria from the cell's main compartment, the cytoplasm. But if too much iron is floating around freely inside mitochondria, it can interact with oxygen-based chemicals and trigger oxidative stress, Isaya explains. Her MDA-supported research suggests that in yeast and in humans, frataxin acts as a storage depot for iron, releasing it only when it's needed.

Iron Chelation

There are clear signs of iron imbalance in people with FA. Although not fully appreciated at the time, studies in the 1980s showed that cells from people with FA contained abnormal iron deposits. More recent studies (on human and yeast cells) have shown that the iron accumulates specifically inside mitochondria. The same features are seen in frataxin-deficient mice, created by Koenig's group.

Early on, these observations caused a lot of excitement over iron chelators — drugs that capture iron and carry it through the body to be excreted.

Unfortunately, one such drug (desferrioxamine, or DFO) failed against FA in a clinical trial, raising skepticism about chelation therapy in general. Moreover, recent studies suggest that the mitochondrial iron accumulation in FA is mirrored by a depletion of iron in other cell compartments. So, some FA researchers worry that iron chelators might actually do more harm than good.

Others believe that the key to making the treatment a success is to develop better chelators than DFO, which removes iron from the cytoplasm, but isn't able to penetrate mitochondria.

"I think [iron chelation] may represent a valid approach provided that the chelator acts specifically on mitochondrial iron without altering other iron pools in the cell," Isaya says.

Des Richardson, an MDA grantee and expert on iron biochemistry at the University of New South Wales in Sydney, Australia, is focused on this kind of research. "We are assessing a newly synthesized group of chelators that target the mitochondrion," he says. "We hope to begin our studies on FA mice very soon so that we can test our hypothesis."

Antioxidants

While Richardson and others continue to refine iron chelators in the lab, antioxidants have taken a more solid place against FA in the clinic. In part, this is because antioxidants are available over the counter and generally considered safe. But it's also because there's such overwhelming evidence for oxidative stress in FA, says Robert Wilson, a geneticist at the University of Pennsylvania in Philadelphia.

"There's a lot of question as to which comes first, the iron buildup or the oxidative damage, and that's still being worked out," says Wilson, who studied yeast frataxin early in his career and is now a lead investigator in the idebenone trial. "But Friedreich's clearly has a component of oxidative stress in mitochondria. Everyone accepts that."

Indeed, frataxin-deficient cells are highly sensitive to chemicals that induce oxidative stress, and in lab experiments, treatment with certain antioxidants has been shown to improve their survival. Recent studies show that two indicators of oxidative stress — malondialdehyde (a breakdown product of cell membranes) and 8OH2'dG (a breakdown product of DNA) — are elevated in blood and in urine from people with FA.

Evidence that antioxidants really work in people with FA is still very preliminary, but many people take them anyway. Two antioxidants, N-acetyl cysteine (NAC) and alpha-lipoic acid, are widely used despite the fact that they've never shown efficacy against FA in published clinical trials. Three others, coenzyme Q10, vitamin E and idebenone, have shown encouraging results in clinical trials overseas.

Coenzyme Q10 (coQ10) is a small molecule naturally present in mitochondria, where it helps combine oxygen with "fuel" from carbohydrates and fat to produce energy. Also known as ubiquinone, it has antioxidant properties and is available over the counter as a dietary supplement.

In a recent trial conducted in England, 10 people with FA received a combination of coQ10 and vitamin E for six months. The treatment didn't alleviate ataxia, but in nine people it improved energy production (measured as an increase in the energy molecule ATP) in cardiac and voluntary muscle.

Idebenone

Idebenone, a synthetic analogue of coQ10, has shown more promise than any other antioxidant. In 1999, French researchers reported that several months of treatment with idebenone significantly diminished the hypertrophic cardiomyopathy (but again, not the ataxia) in three young people with FA. More recently, the French group reported similar results from a trial involving nearly 40 people with FA, and a German-American team reported that two months of idebenone reduced urinary levels of 8OH2'dG in eight people with FA.

Those results led to the current U.S. trial of idebenone, a collaborative effort between Wilson and Kenneth Fischbeck, chief of the Neurogenetics Branch at the National Institute of Neurological Disorders and Stroke (NINDS) at NIH.

Phase 1 of the trial will primarily test idebenone's safety (not its efficacy) but with a twist: Fischbeck and his colleagues will go beyond the dose tested in the French trials and determine the maximum tolerated dose. It's hoped that in phases 2 and 3, which will be placebo-controlled, this large dose of idebenone will prove effective against cardiomyopathy and ataxia.

In phase 1a, currently under way at the NIH campus in Bethesda, Md., participants receive a single, oral dose of idebenone for just one day. After one dosage level looks safe, a new group of participants comes in to receive the next dosage level. In phase 1b, participants will receive daily idebenone for a week or two, Fischbeck says.

The trial is fully enrolled for adults and adolescents, but as of this writing, is still recruiting children ages 5 to 11. (For more information, visit the "clinical trials" section of MDA's Web site at www.mda.org/research/ctrials.aspx, or NIH's clinical trial site at www.clinicaltrials.gov.)

Since the Kiernans live near Bethesda, Erin registered for the trial, and by luck of the draw, she was selected to participate in phase 1a.

"They didn't see any [side effects] so I'm guessing that idebenone should be good, but we don't know yet because it's still being tested," Erin says. "Hopefully, it'll work so that we can give it to other people with FA." (For more on idebenone and the Kiernans' feelings about it, see "Is Idebenone Worth Waiting For?")

Wilson, who will direct phase 2 of the trial, is cautiously optimistic about its outcome. "I don't think idebenone is going to cure [FA], but I think it will be an effective treatment," he says.

He's far more optimistic about the general future of FA therapy, noting that basic research on the disease has opened many doors.

"Nobody was talking about antioxidants or iron chelators until we understood that [FA] involves iron and oxidative damage," he says. "The more we understand about the underlying biochemistry of FA, the more therapeutic possibilities suggest themselves. This is just the beginning of the treatment era for this disease."