16 March 2012. As tau twists and tangles within neurons in the brains of Alzheimer’s disease patients, it loses its ability to firm up microtubules—but a brain-penetrant cancer drug could come to the rescue. In this week’s Journal of Neuroscience, researchers led by Kurt Brunden at the University of Pennsylvania School of Medicine, Philadelphia, report that epothilone D reverses behavioral and cognitive deficits, clears tau pathology, and curbs neuron loss in older tau transgenic mice. Earlier, the scientists had reported that the microtubule-stabilizing agent improves symptoms and pathology in young PS19 mice (see Brunden et al., 2010 and ARF conference story), but the current study suggests the compound can also help older tauopathy mice with established disease. “Thus, the study can be thought of as ‘interventional’ as opposed to the 2010 paper, which was a ‘preventative’ study design,” Brunden noted in an e-mail to ARF. “This interventional design is a tougher test for a drug candidate, and more closely mimics the human clinical situation where patients typically present with signs of the disease.” Brunden presented some of the data in old PS19 mice at a tau workshop in San Francisco last spring (see ARF conference story).
First author Bin Zhang and colleagues gave intraperitoneal injections of epothilone D to nine-month-old male PS19 mice once a week for three months. Typically, scientists see axonal damage in this transgenic strain by three months of age, and spatial learning impairment develops by six months (Brunden et al., 2010). In the current study, treated PS19 mice retained more intact axons, lost fewer hippocampal neurons, and did better on working memory and spatial memory tests compared to vehicle-treated transgenics or wild-type controls. The compound caused no adverse effects in the mice, which received doses 30- to 100-fold lower than those used for cancer patients. Earlier, the scientists had reported that it has good pharmacokinetic properties, sticking around in the brain at least a week after a single administration (Brunden et al., 2011).
Bristol-Myers Squibb is currently enrolling for a Phase 1b trial of epothilone D in mild AD patients. The study will evaluate the compound’s safety and pharmacodynamics, as well as its impact on cerebrospinal fluid levels of tau, brain connectivity, and cognition after nine weekly intravenous infusions.—Esther Landhuis.
Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AL, Xie SX, Ballatore C, Smith AB, Lee VM, Brunden KR. The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice. J Neurosci. 14 Mar 2012;32(11):3601-3611. Abstract