Our knowledge of the tau protein and the tauopathies is expanding faster than ever.  In February 2020, just before the lockdown, the Alzheimer Association, the Rainwater Charitable Foundation and CurePSP hosted an international conference in Washington, DC to discuss the latest in tau-ology.  “Tau2020” drew 650 people from 21 countries – academic researchers, government regulators, lay organization leaders, philanthropists, and key players in the pharmaceutical and biotech industries. 

A 12,000-word article summarizing the two days of talks appeared last week in the journal Alzheimer’s and Dementia.  In this post and the next, I summarize that summary – with an eye in particular on PSP and CBD, though much of the conference’s attention, understandably, was on Alzheimer’s disease and frontotemporal dementia. What follows is not a textbook article nor literature review or even a summary of one, but only a list of recent advances presented at the Tau2020 conference.

Today’s post will cover treatment issues and tomorrow’s will cover everything else. Dickens, Dostoevsky, Hemingway, Joyce, and Nabokov published in installments – why can’t I?  

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The failure in clinical PSP trials of two monoclonal antibodies directed against tau’s N-terminal (i.e., the “beginning” or left end of the molecule as conventionally depicted) has not prevented researchers from developing antibodies against other parts of the tau molecule. Antibodies against (in conventional left-to-right order) the proline-rich region, the microtubule binding region or the C-terminal region are all under investigation. We now know that antibodies directed against the central regions of tau are more effective in preventing tau spread in cultured human neurons.  In fact, administering a mixture of antibodies directed against more than one of these regions is being contemplated. 

The two trials that ultimately failed in PSP chose the N-terminal as the target for their antibodies because in Alzheimer’s disease, misfolding starts in that area and because fragments of tau that include the N-terminal increase beta-amyloid production, an observation irrelevant to PSP.  Perhaps for these reasons, the two companies have continued their AD programs for their N-terminal-directed antibodies while discontinuing their PSP programs.  In my opinion, this is another potential difference between AD and PSP that weakens the hypothesis that a tau-directed prevention of either will be a prevention for both.

Several conference speakers emphasized that going forward, our ability to detect a neuroprotective benefit of any tau-based drug will improve if the clinical trials can manage to exclude non-tauopathy patients with disorders mimicking a tauopathy.  Such patients include those with dementia with Lewy bodies, multiple system atrophy, TDP-43-based frontotemporal dementia, normal-pressure hydrocephalus and vascular parkinsonism.  The speakers also agreed that new diagnostic markers will have to detect disease at a much earlier stage to give patients the greatest likelihood of responding while still able to live a good-quality life.  They also felt that future trials should avoid subjects taking many concomitant medications that could obscure the benefit of the drug being tested.  A further recommendation was to tailor the specific outcome measure to each patient’s combination of deficits and that the various subtypes of PSP, each of which may have its own mode of tau spread, are unlikely to respond equally to the same neuroprotective agent.  Finally, they noted that we do not yet know how far tau must be reduced to achieve slowing of disease progression, and that this may vary across patients.

Another active area, but so far applied only to AD, is active anti-tau vaccines.  This is where a person with or without disease receives an inactive fragment or form of tau, inducing the immune system to make antibodies directed against disease-causing tau that persist for months, years or decades.  This is the mechanism for most vaccines in common use.  It differs from the monoclonal antibody-based passive “vaccination,” where antibodies themselves are infused from the outset and typically wear off in a month or so.  Probably the active vaccine furthest down the clinical pipeline is ACI-35, from Axon Neuroscience.  Again, trials so far are in AD and no plans to extend them to PSP have been announced.

Anti-sense oligonucleotides (ASOs) have entered early clinical trials in both PSP and AD.  ASOs are short, single-stranded synthetic DNA molecules.  They bind to the messenger RNA that that assists in the production of tau, in turn inducing the enzyme RNase H1 to degrade that mRNA.  Unfortunately, ASOs can only be given by injection into the spinal fluid, as they cannot cross the blood-brain barrier.  The procedure must be repeated every three months. Another potential drawback is that ASOs reduce production of normal tau as much as they do abnormal tau. A Phase 1 safety and tolerability trial in 64 patients is being conducted at Mayo Clinic Rochester, Vanderbilt University and at two sites in Canada, three in Germany and one in the UK. For more information, visit http://www.clinicaltrials.gov (www.ClinicalTrials.gov Identifier: NCT04539041).

A highly innovative solution to the problem crossing the blood-brain barrier that limits utility of the ASOs and many other potential new neurological drugs.  Denali Therapeutics is testing a “transport vehicle,” a molecule that can escort a variety of drugs across the BBB.  It works by binding to an antibody with the “transferrin receptor” protein genetically engineered into its structure.  The therapeutic drug is then bound to this complex, which can penetrate the BBB.  Denali is experimenting with attaching anti-tau antibodies or tau-directed ASOs to this vehicle. Trials in humans have not yet begun.

Another approach that sounds like science fiction is “proteolysis-targeting chimeras (PROTAC) molecules, first developed in 2001.  These are hybrids of two small molecules, one of which can bind to, in this case, tau, and the other that is recognized by the brain cells’ internal garbage disposal called the ubiquitin-proteasome system.  Unlike antibodies, PROTACs can easily enter brain cells.  Their only human application so far has been in oncology, but experiments in mouse tauopathy models are proving successful.

A new methodology in clinical trial design is the “basket study,” common in oncology, where several rare types of cancer are tested as a group.  We still know too little about the differences among the tauopathies to insist that in evaluating a new drug, each disease must have its own trial.  The one basket study to date that included PSP was performed at UCSF for the drug TPI-287, which stabilizes microtubules.  AD, PSP and CBS were included.  Unfortunately, the drug proved inefficacious, but the trial method proved practical.