Science Editor

Last week Medivation Inc. said its mitochondria-targeting drug candidate, Dimebon, was shown to be safe and well tolerated and also significantly improved cognitive function compared to placebo in a Phase II study. (See BioWorld Today, July 9, 2008.)

And at the same time, a paper added basic research to the evidence that targeting mitochondria can be a promising strategy in Huntington's, while an additional study implicated a hyperactive innate immune response in the disease.

In the first study, published in the July 7, 2008, online edition of the Journal of Biological Chemistry, researchers from Magdeburg, Germany-based biotechnology company KeyNeurotek Pharmaceuticals AG reported on how huntingtin, the protein that is mutated in Huntington's disease, might damage neurons by wreaking havoc with energy generation in mitochondria, the energy powerhouses of the cell.

Mutant huntingtin has been found on the surface of mitochondria, first author Frank Gellerich explained to BioWorld Today, but what it was doing there - and whether it was doing anything at all related to Huntington's disease - was unclear. When Gellerich, head of the department of energy metabolism at KeyNeurotek, and his colleagues created a new mouse model and studied the mitochondria in more detail, they found that by interacting with an amino acid transporter and a calcium pore, the huntingtin affects ATP generation in several ways.

In order to provide energy for the cell, "Mitochondria need oxygen, ATP . . . and mitochondrial substrate" in the form of an oxidizable amino acid, Gellerich added. Extracellular calcium can influence that energy metabolism.

Mutant huntingtin appears to influence that process in several ways. "It makes mitochondria more vulnerable to calcium stress, and that is probably the most dangerous" of its effects on mitochondria, Gellerich said. But it also decreases amino acid entry, thus depriving the mitochondria of a key substrate for ATP generation.

Given that mitochondria are a mainstay of cells everywhere, why Huntington's affects striatal neurons so much more that other cell types is "difficult to explain," Gellerich acknowledged. In separate work, Gellerich and his colleagues have shown that skeletal muscle also is affected in Huntington's disease. One possibility is that striatal neurons are simply the canary in the coal mine, and the deleterious effects of mitochondrial problems show up later in other tissues.

In a separate study published in the July 14, 2008, issue of the Journal of Experimental Medicine, a team of British, American, Swedish and Canadian researchers showed that at least one additional cell types is affected in Huntington's disease: cytokine-producing cells of the immune system.

Starting from the observation that patients with Huntington's disease have brain inflammation and higher levels of brain cytokines, the scientists investigated plasma levels of a number of cytokines in carriers of mutated huntingtin and controls.

A number of cytokines were increased in the plasma of individuals with mutated huntingtin, with changes in the innate immune system apparently coming before those in the adaptive immune system. Immunoglobulin levels remained normal, suggesting, the authors said, that "there is no generalized activation of the immune response" in Huntington's.

Both isolated monocytes from huntingtin mutation carriers, and both macrophages and microglia from mouse models of Huntington's, all had a stronger cytokine response to stimulation than controls.

Increased interleukin-6 levels in patients appeared a decade and a half before the estimated onset of symptoms, making them the earliest plasma level abnormalities detected in such carriers to date and a useful biomarker. "There is a need for markers of progression ("state biomarkers") in [Huntington's Disease] and other neurodegenerative diseases," the authors wrote. "Our results suggest that inflammatory changes detected in peripheral plasma may be biologically relevant and mirror the neurodegenerative process occurring in the CNS."

Asked about the mechanism by which huntingtin sends innate immune system cells into overdrive, co-author Thomas Moeller, of the University of Washington, told BioWorld Today, "nothing I can share at this point. But, of course, this is what we are currently working on. We speculate that huntingtin is interacting with transcriptional activators and/or repressors." As to whether it is a possibility that the same relationship to calcium exists here that was described in the Journal of Biological Chemistry paper, he said that "I have worked on calcium signaling in microglia for quite some time now. . . . So of course we are thinking along these lines."