PET Imaging Used to Assess Effectiveness of Menkes Disease Treatments

Copper distribution is deregulated in a genetic disorder called Menkes disease (MD). This study provides the groundwork for PET imaging studies on human MD patients to identify new therapy approaches.

Although rare, Menkes disease, is a formidable genetic disorder. Most affected infants die within the first few years of life. The disease is caused by an inborn defect in the body’s ability to absorb copper. The standard treatment today for the 1 in 100,000 babies affected by the disorder is to inject copper, but this therapy has limited efficacy. Eventually the treatment becomes ineffective, leading to neurodeneration, and the copper accumulates in the kidneys, sometimes leading to renal failure.

The resulting treatments have been found to enhance the accumulation of injected copper in the brain while preventing its accumulation in the kidney. Recently, disulfiram, a medication developed to treat alcoholism, has been proposed as a therapy for MD, since one of its actions is to enhance this copper accumulation in the brain.

Now, in a new study published April 1, 2014, in the Journal of Nuclear Medicine, scientists from the RIKEN Center for Life Science Technologies (Kobe, Japan), working with pediatricians from Osaka City University (Japan) and Teikyo University (Tokyo, Japan) employed positron emission tomography imaging (PET) imaging to show that a combination of copper injections and disulfiram or D-penicillamine allows a greater movement of copper to the brain, where it is needed, without accruing in the kidneys.

In the study, the researchers used Menkes disease model mice, which have an inborn defect in copper metabolism, and injected copper-64, a radioactive isotope of copper, into the mice. They then used PET scanning, a noninvasive procedure, to visualize how the copper traveled throughout the body. They compared mice injected with copper alone to mice injected with copper in addition to one of two other drugs, disulfiram, or D-penicillamine, and the copper distribution throughout the body was observed for a four-hour time period.

The findings revealed that the mice administered the copper combined with disulfiram had a comparatively high concentration of copper in the brain without a substantial increase in the kidneys. Remarkably, it revealed that the amount of copper going to the brain in mice treated with disulfiram was in reality higher than in those treated with copper by itself, suggesting that the agent has an effect on the passage of copper through the blood-brain barrier.

According to Dr. Satoshi Nozaki, one of the co-authors, “This study demonstrates that PET imaging can be a useful tool for evaluating new treatments for Menkes disease.” Planning for the future, he said, “Based on this study, we are planning to conduct clinical PET studies of patient with Menkes disease.”

Related Links:
RIKEN Center for Life Science Technologies
Osaka City University 
Teikyo University