Now that CurePSP’s December 1 deadline for its next semi-annual crop of grant applications has passed, I’ll try to finish reporting on the crop of funded projects from July’s deadline. 

This one’s pretty cool.  It tests an FDA-approved drug for AIDS called efavirenz (brand name, Sustiva) for  its ability to prevent tau from aggregating and causing brain cell loss in a mouse model.  The principal investigator is Rik Van der Kant, PhD of the Vrije University in Amsterdam.  Like most of CurePSP’s grant recipients, he’s relatively junior, having completed his PhD in 2013 and his postdoctoral training only in 2019.

Dr. Van der Kant and his colleagues have shown that efavirenz improves degradation of tau in brain cells that were created from human stem cells.  In fact, the drug is already in a very small, early-phase clinical trial for Alzheimer’s disease at Case Western and at Mass General. That trial was expected to finish in December 2020 (this month), but I assume that the Covid lockdown has delayed that.

The new project will give efavirenz to P301S mice.  Those critters carry not only their own normal mouse tau gene, but also a human gene for tau with a mutation that causes a PSP-like illness in people.  (It’s actually a familial form of frontotemporal dementia that closely resembles PSP.)  Tau P301S mice are probably the best PSP model we have at present, all things considered, though stem-cell-based models are gaining fast.

The tauopathy-prone mice will receive either efavirenz or a control solution in their drinking water from age 3 months to 6 months.  After another 3 months, they will be tested for their motor and cognitive abilities and their brain tissue will then be analyzed for tau, phosphorylated tau, number of neurons and synapses, and for the efficiency of one of their brain cells’ garbage disposal mechanisms, the proteasomal system.  Dr. Van der Kant’s hypothesis is that efavirenz revs up the proteasomal system by reducing cholesteryl esters.  Evidence from his stem cell work supports that idea, but he would now like to investigate this in a whole animal.

The next step, not covered by the current grant, would be a trial in people with PSP.  Efavirenz reached the US market in 1998 and has been available as a generic since 2016.  It crosses the blood-brain barrier and is acceptably safe and well-tolerated in patients with AIDS.  There’s no reason to suspect that those with PSP wouldn’t tolerate it as well, but we can’t just assume that.  Of course, as a generic, it may be difficult for efavirenz to find funding for clinical trials for a new indication.  CurePSP might be willing to chip in what it can, but their maximum grant is $100,000, while the median phase II trial costs $8.6 million and the figure for phase III trials is $21.4 million.  Sometimes this problem is solved when a deep-pocketed drug company invents a new version of the drug that works the same but is chemically different enough to win a new patent. 

But first let’s all hope the drug works in the P301L mice.  Pessimism alert: Maybe in a future post, I’ll opine on why davunetide, tideglusib and two monoclonal antibodies worked in similar mice but not in human PSP.  That’s one of the biggest questions in PSP research right now.