A Cytochrome P450 Therapeutic Space for Tauopathies

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A Cytochrome P450 Therapeutic Space for Tauopathies Project Summary In the 30 years since Tau was first identified as a key constituent of neurofibrillary tangles—and subsequently a causative agent of neurodegeneration—the Tauopathy field has made important strides in understanding how abnormal forms of Tau protein lead to damage. Tau interacts in complex ways with other cellular constituents and with surrounding cells within the brain. This complexity makes developing tauopathy therapeutics especially challenging. Currently there are no therapies that strongly alter disease progression: approved treatments such as cholinesterase inhibitors and the NMDA receptor antagonist memantine show modest symptomatic benefit in patients with early- to mid-stage Alzheimer’s Disease. New efforts include reducing Tau mRNA expression, reducing insulin-associated metabolic deficits, addressing abnormal Tau phosphorylation and, in recent clinical trials, targeting the spread of pathogenic Tau protein with immunotherapy. To date, these approaches have yielded limited efficacy, Pathophysiological changes in the brain precede cognitive impairment by years or even decades, presenting a broad temporal window for treatment. Tools including PET, chemical tracers and mass spectrometry assays are being developed to detect prodromal pathogenic Tau isoforms in situ. Focusing on Mendelian forms of tauopathy presents a still broader temporal window for treatment. One promising approach to reducing long-term toxicity is targeted therapies, for example against Tau protein itself. However, Tau protein is fundamental to a cell’s physiology and the therapeutic window of Tau-specific therapies may prove limited. Our laboratories are working to create an integrated approach to both understand the biology of tauopathies and to develop new lead compounds. Regarding the latter we are using the Drosophila TauR406W platform as a whole animal model to identify drugs that can reduce Tau-dependent neuronal damage. An especially promising hit is the FDA approved drug Anastrozole, an inhibitor of the cytochrome P450 Aromatase. We further demonstrated the effectiveness of Anastrozole to reduce dysfunction in an iPSC- derived TauR406W model. Remarkably, this Tau rescue did not dependent on Anastrozole’s inhibition of Aromatase, indicating Anastrozole is acting through off-target activities, suggesting the potential for an improved Anastrozole analog. We propose to use our novel fly/chemistry platform to ‘evolve’ an improved Anastrozole analog (‘anastrolog’) that better addresses Tau-mediated damage in the context of the whole animal while retaining at least some of Anastrozole’s favorable properties.