Funded by the A-T Children’s Project, Howard Lederman, MD, PhD, Director of the A-T Clinical Center at Johns Hopkins Hospital in Baltimore, Maryland, is  studying how a combination of two dietary supplements, an antioxidant and a PARP-1 inhibitor can slow the neurodegeneration and aid the pulmonary problems seen in patients with A-T.

For several years, a growing body of evidence has accumulated which suggests that oxidative stress may contribute to the pathology of ataxia-telangiectasia (A-T). Oxidative stress, which can ultimately lead to cell death, occurs when cells cannot properly detoxify reactive oxygen species (ROS). ROS are highly reactive chemicals which move about the interior of cells causing damage to cellular DNA (genetic material), lipids and protein. Regardless of whether oxidative stress is a primary or secondary result of ATM protein deficiency, research has shown that abnormalities exist in the oxidative state of various A-T model systems.

In addition, a recent study has also shown that in cultured A-T cells, there is an increase in the activity of the poly (ADP-ribose) polymerase (PARP-1) enzyme. Like ATM, this enzyme plays an important role in the cellular response to damaged DNA. In A-T cells, the increase in PARP-1 activity was accompanied by an observed decrease in important cellular energy stores. Treatment of the ATM deficient cells with various PARP-1 inhibitors enhanced the growth rates of these cells in culture.

As a result of the research described above, the A-T Clinical Center has prepared a trial protocol to test the efficacy of an antioxidant/PARP-1 inhibitor combination in A-T patients. To date, only anecdotal evidence exists suggesting that antioxidants have any type of positive effect in children with A-T, i.e. this evidence has come from parents who have been giving their children with A-T antioxidants such as vitamin C, E and alpha lipoic acid. The advantage of the trial at Johns Hopkins is that the combination, dosage and efficacy of the antioxidant/PARP-1 inhibitor combination will be evaluated in a clinically objective and quantitative manner. Although the ultimate goal of this trial is to determine if this treatment can slow disease progression in A-T patients, the clinical trial will also test the possibility that these compounds will have an immediate, positive effect.

The clinical study began with a Phase I trial designed to assess the safety and toxicity of nicotinamide (a PARP inhibitor) and alpha lipoic acid (an antioxidant). During the trial, it will be important to determine if the combination of drugs used is having a biological effect in the patients that eventually might produce an overall positive result in terms of disease progression. Therefore, quantitative laboratory endpoints will be evaluated to determine the drug’s biochemical efficacy. These biochemical endpoints will include specialized blood and urine tests to detect oxidative damage to cellular lipids and DNA. Tests will be performed to monitor changes in neurologic and pulmonary function, and to look for any toxicity of the combination of drugs.

The initial Phase I trial will last 8 1/2 months. Since the main objective is to determine safety and toxicity, a relatively small number of patients (20) will be enrolled, and the focus will be on teenagers and adults. If positive results are seen at the end of this trial, the study will be expanded to include more patients and a younger patient population. If, however, there are no changes in the biochemical endpoints or toxicity becomes an issue during the trial, then drug and or dosage modifications will be made.

It is hoped that this initial trial produces positive results, leading to a much larger study investigating the treatment of A-T.