Grants and Contracts Details
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that leads to profound cognitive deficits and ultimately death. There is presently no cure for AD. Much recent work has centered on therapies that directly target the hallmark amyloid-(Abeta) plaque features of the disease. However, results from clinical trials using these approaches have been disappointing; suggesting that the pursuit of other molecular mechanisms and/or novel therapeutic approaches would be prudent. In this project, we propose to use a novel compound, Q134, developed by Avidin Ltd to target an alternative mechanism for AD pathophysiology: i.e. the Nuclear Factor of Activated T cells (NFAT). NFATs are a family of transcription factors that are specifically activated by the protein phosphatase calcineurin (CN). In peripheral tissues, CN/NFAT interactions coordinate the adaptive immune response and are the primary targets of the staple immunosuppressant drugs, tacrolimus and cyclosporine, used to prevent solid organ transplant rejection. In addition to peripheral immune signaling, the CN/NFAT pathway also plays a key role in regulating diverse transcriptional programs in resident neural cells. Several recent studies across independent laboratories have found that CN activity and/or expression is increased in human AD brain and associated with the progression of dementia. Importantly, we have observed signs of hyperactive CN/NFAT signaling in human hippocampus at the outset of clinical symptoms, suggesting that alterations in CN/NFATs arise early in the disease when pharmacological treatments may be most effective. In addition to a clear association with human disease hallmarks, there are at least four general lines of evidence (gleaned from dozens of studies) showing a necessary and sufficient role for aberrant CN/NFAT signaling in AD pathophysiology. First, CN/NFATs are strongly activated in primary neural overexpression of activated CN in nervous tissue recapitulates key biomarkers of AD including glial activation/neuroinflammation, synapse dysfunction, neurodegeneration, and cognitive decline. Third, all of these biomarkers and others (e.g. amyloid pathology) are ameliorated in AD animal models via genetic or pharmacologic inhibition of CN/NFAT signaling. And finally, epidemiological data shows that kidney transplant patients treated with commercial CN inhibitors (CNIs) are far less likely to develop dementia than age-matched subjects in the general population. Together, these findings suggest that the CN/NFAT pathway is a promising molecular target for anti-AD therapeutics. In this regard, commercial CNIs (tacrolimus and cyclosporine), which are already FDA-approved, seem like a natural option for further clinical investigation. However, the severe adverse effects profile of oral CNIs has dampened enthusiasm for their use outside of allograft transplant cases. The novel compound, Q134, exhibits NFAT inhibitory properties, but does not appear to suppress CN activation per se. The greater selectivity of Q134 over commercial CNIs suggests a more favorable adverse effects profile that would be better-suited for long-term use in humans at risk for AD-type dementia. This proposal will use a preclinical AD mouse model as an important test of the potential clinical efficacy of Q134.
|Effective start/end date||3/15/17 → 3/15/18|
- Alzheimers Drug Discovery Foundation: $257,552.00
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