10 April 2008. To borrow IT-speak, “repurposing” is an underused art in Alzheimer disease drug research. Drugs that have proven to be reasonably safe and effective in one condition could be tried for AD, as well. Such drugs tend to target aspects of AD that this disease has in common with other conditions, for example, its inflammatory component, potentially making them suitable for future combination therapies. One such drug is CNI-1493 (aka semapimod), a synthetic anti-cytokine that has been tested for conditions including Crohn’s inflammatory bowel disease, rheumatoid arthritis, and psoriasis. CNI-1493 is a tetravalent guanlhydrazone that inhibits signaling through the p38 MAP kinase pathway and suppresses release of inflammatory cytokines such as TNFα or certain interleukins from macrophages. At the Keystone conference held 24-29 March in Keystone, Colorado, Michael Bacher of Philipps University in Marburg, Germany, suggested that the drug binds tightly to Aβ oligomers and could be explored for potential future trials in AD.
The drug has been tested in Phase 1 and 2 trials for Crohn’s, but human testing stumbled over local side effects to the infused drug formulation. Recently, the company developing the drug came up with an oral preparation and is now trying to resume clinical trials.
Bacher reported first testing CNI-1493 in cell lines overexpressing APP. The compound left APP processing unchanged but, in dose-dependent fashion, reduced levels of secreted oligomers as detected by the A11 antibody (Kayed et al., 2003). Then Bacher and colleagues treated CRND8 mice with the drug for eight weeks between four and six months of age, when this model progresses from moderate to advanced disease (McLaurin Keystone story). Bacher reported seeing a drastic reduction of soluble brain Aβ levels, as well as of plaques in cortex and hippocampus. Bacher showed no data on the Morris water maze but reported that the treated mice performed better on a novel object recognition task. Besides binding to Aβ, the compound also pacifies microglia in the brain, according to Bacher; however, no detailed cytokine analysis was performed to characterize the microglial response in this mouse model further. In this initial study, the scientists did not yet look for changes of Aβ in plasma or effects on CAA. According to Bacher, this data is in press at the Journal of Experimental Medicine.—Gabrielle Strobel.