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LMG Researcher Reports on Clinical Trial of Antioxidant in Friedreich's Ataxia

By Eddy Ball
February 2007

Ben Van Houten
LMG Principal Investigator Ben Van Houten (Photo by Eddy Ball)

chart of genes expressed in higher patients
This figure is a tree-view rendering of microarray data, showing supervised clustering of some of the 142 most significantly changed genes (red indicates induced, green repressed) in Control (Cont) subjects and Friedreich's patients before and after treatment with idebenone. Note the dramatic contrast between pre-treatment/placebo results (predominantly red) and the post-treatment dose-dependent increases in green. (Graphic courtesy of Ben Van Houten. mRNA hybridizations on to oligonucleotide microarray chips performed at NIEHS by Rick Fanin; gene expression analysis conducted by Astrid Haugen of NIEHS and Joel Parker of Constella Group)

At his lecture on January 10 in Rall D-350, Laboratory of Molecular Genetics Principal Investigator Ben Van Houten, Ph.D., reported on the results of his group's recent collaboration with researchers from a sister institute in a phase 2 double-blind, placebo-controlled clinical trial. Utilizing advanced technology available at NIEHS, the team completed studies of gene expression that show potential for clinical application in monitoring patient response to treatment.

The study examined the efficacy of an antioxidant intervention, idebenone, for Friedreich's ataxia, a progressive neurological disease. As part of an NIH Bench-to-Bedside award, teams of intramural researchers from NIEHS, led by Van Houten, and the National Institute of Neurological Disorders and Stroke (NINDS), led by Nicholas Di Prospero, M.D., Ph.D., and Kenneth Fischbeck, M.D., evaluated clinical and molecular endpoints in the first clinical trial of its kind involving the controversial alternative treatment.

The collaborative study followed 48 subjects, aged 9 to 11 and 12 to 17 years, in four treatment arms over a period of six months. Participants received placebo, low, intermediate or high doses of the antioxidant. Because of restrictions on drawing blood from healthy children for clinical trials, researchers used a group of ten 18- to 25-year-old healthy individuals as controls.

All of the subjects had manifest symptoms of the neurological disorder, an iron-homeostasis disease caused by a mutation in the gene for frataxin, an iron-binding protein. In patients with Friedreich's, frataxin is not sufficiently available to load iron, starving cells of the mineral and leading to the accumulation of iron in the mitochondria.

The teams conducted the study at the NIH Clinical Center in Bethesda, where over a period of two days subjects underwent a battery of testing and sample collection for laboratory studies. The tests included a very sophisticated cardiac output assessment, several different measures of gait and a number of neurological batteries. Testing and sample collection took place at the beginning of the study and six months later. The researchers drew blood for RNA, DNA and serum analysis and collected urine samples.

Van Houten and colleagues in his lab took RNA from lymphocytes and performed gene expression profiling at NIEHS. They also sent serum and urine to a contract lab for metabolic profiling and analysis of low molecular weight metabolites. Using lymphocytes as a surrogate marker for damage to heart tissue, the researchers looked for evidence of chronic mitochondrial DNA damage from cumulative free radical oxidation and iron overload.

Using Significance Analysis of Microarray, the NIEHS team determined that there were 6,000 gene expression changes that differed between controls and subjects. Researchers employed ANOVA analysis to narrow that number to the 600 most significantly different genes. They then selected a set of 142 genes that could give researchers the most information about differences between patients and controls and between pre- and post-treatment gene expression.

Looking at the results, the researchers discovered that the gene expression patterns of most of the low-, medium- and high-dose subjects showed patterns similar to controls after treatment, while the placebo group's results looked the same as or worse than treatment subjects' results prior to dosing. There were a small number of non-responders, but the averaged gene expression data confirmed the efficacy of treatment, the blunting of the pro-inflammatory state and the dose-dependency of response. This study is especially exciting, according to Van Houten, because heretofore the pro-inflammatory state of these patients had not been fully appreciated and the study suggests a potential new strategy for therapy.

Significantly, the gene expression outcomes corresponded to the clinical and metabolic outcomes. Neurological measures showed improvement in gait and motor control, and there were significant changes in metabolites measured in serum and urine. Van Houten's lab also identified nine "responder" genes whose expression may help discriminate between patients who are benefiting from treatment and patients who are not responding to the intervention.

The clinical trial produced surprising results for Van Houten and his team. He explained, "We saw a really big difference between patients and controls at the beginning of the study, and that was exciting. We also could track changes in gene expression that corresponded with treatment and to improvements in clinical measures."

Friedreich's Ataxia

Named for German physician Nikolaus Friedreich (1825-1882), who first described the condition in the 1860s, Friedreich's ataxia is a rare, inherited disease that strikes about 1 in every 50,000 people in the United States. "Ataxia" refers to coordination problems that can range from unsteadiness to complete loss of motor control. Friedreich's ataxia is the most prevalent form of inherited ataxias, and it appears equally in males and females.

Infants with Friedreich's ataxia are outwardly normal at birth. However, as they grow into childhood and early adolescence, symptoms of the disease begin to appear. The disease initially affects the nervous system, leading first to an altered walking gait and later to speech problems and muscle problems as the damage to nerve tissue in the spinal cord and to nerves that control movement in the arms and legs becomes more severe. The disease is caused by a reduction of a critical iron homeostasis protein, frataxin, found in the mitochondria.

As Friedreich's ataxia progresses in patients, they may lose the muscle control necessary to speak, read or walk. Although the rate of progression of the disease varies, many patients are forced to use a wheelchair a decade or two after symptoms appear and eventually may become completely incapacitated. The most common cause of death is heart attack due to enlarged heart (hypertrophic cardiomyopathy), usually in middle age (mean 38 years old).

There is no cure for the disease, and, although some of the symptoms can be treated with medications or physical therapy, currently available treatment does little to increase lifespan or improve patients' diminishing quality of life.

In addition to the clinical trial conducted by NINDS/NIEHS, researchers at the Necker Hospital in Paris are currently recruiting volunteers for a study on the efficacy of iron chelation to improve central nervous system function.


Idebenone is an analogue of CoQ10, a far better known and more popular over-the-counter antioxidant, but it is even more effective at inhibiting lipid peroxidation and has been shown to stimulate cardiac function. Many parents self-administer their Friedreich's ataxia children with the compound because the sale of idebenone is not regulated by the FDA, and they can purchase the supplement without restriction on the web. Practitioners in Japan have used the compound with Parkinson's and Alzheimer's patients, and there are many anecdotal reports of its efficacy in ataxia disorders, possibly by enhancing electron transport in the mitochondria.

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