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Hernandez I, Luna G, Rauch JN, Reis SA, Giroux M, Karch CM, Boctor D, Sibih YE, Storm NJ, Diaz A, Kaushik S, Zekanowski C, Kang AA, Hinman CR, Cerovac V, Guzman E, Zhou H, Haggarty SJ, Goate AM, Fisher SK, Cuervo AM, Kosik KS. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med. 2019 Mar 27;11(485) PubMed.
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UCSF
This is an elegant study that clearly demonstrates the potential role of cellular protein degradation mechanisms in regulating tau pathology. While it is encouraging that lonafarnib is already approved for use in humans for other indications and might therefore be repurposed for use in human tauopathy patients, as pointed out by the authors, the drug was only effective if started prior to the onset of tau pathology.
While theoretically it might be possibly to adopt such a prevention strategy in human MAPT mutation carriers, strictly speaking, we don’t know when tau pathology begins in these individuals, which makes it very challenging to know when to intervene. There are numerous other challenges to clinical trials in MAPT mutation carriers, including the rarity of these individuals and their clinical and neuropathological heterogeneity that is strongly related to which MAPT mutation is present.
It would be of interest to consider lonafarnib, or another agent that works via a similar mechanism, for other tauopathies such as AD, CBD, nfvPPA, PSP, or CTE, however, the translatability of findings in transgenic mouse and iPSC models to sporadic human tauopathies is uncertain.
A final challenge is the lack of target engagement and other pharmacodynamic biomarkers that can assess whether a drug such as lonafarnib is engaging its target in the human brain and exerting the same biological effects on protein degradation as seen in the preclinical models. I would advocate for increased focus on early identification of such target engagement biomarkers for new therapeutic entities targeting tau in preclinical studies such as this one, if there is a desire to rapidly translate the findings to the clinic.
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