Here are some very quick research updates from the Tau 2022 meeting of February 22-23. Most of this is unpublished, so I can’t get into much detail.
Oral tau expression modulators. Drugs that modulate the production of the tau protein are currently in clinical trials but are administered by injection, typically directly into the spinal fluid. Not very practical. But now, orally administered drugs that do much the same thing are being developed and have drug company interest.
New drug trial?. A drug called lonafarnib, which inhibits an enzyme called farnesyl transferase, is FDA-approved for one form of pathologically early ageing in children. It has also been known for a couple of years to slow progression in a mouse model of tauopathy by enhancing the action of lysosomes, which break down excessive tau. Now, it’s being studied in healthy human volunteers and a trial in people with tauopathies may not be far off.
A tau inflection point. In Alzheimer’s disease, positron emission tomography (PET) scanning for tau has shown that in the first few years, before the symptoms become very troublesome, the tau burden in the brain is increasing slowly. But then, at about the time the symptoms bring the person to medical attention, the tau burden dramatically increases and continues to do so thereafter. That tipping point has been informally and perhaps disrespectfully called a “ca-tau-strophe” beyond which the process may not be amenable to slowing by any treatment. We don’t know if the same thing happens in PSP, but it seems likely. This is further justification for improving the sensitivity of diagnostic methods and for better educating health professionals about PSP.
New gene “knock-in” models. Frontotemporal dementia is strongly hereditary in about a third of cases. Of these, 4% have a PSP-like picture, 5% are PD-like and 2% are CBD-like. The average onset age of hereditary FTD is only 50, compared with about 65 for true PSP. (True PSP occurring in a familial pattern is much rarer and no mutation for that has been identified.) So far, 71 different mutations in the tau gene have been found as causes of hereditary FTD. A few of those have individually been inserted into mice to create commonly used models for PSP and Alzheimer’s research. Those mouse models have taught us a lot, but drugs that slowed progression of the tauopathy in such mice have uniformly failed in human clinical trials of AD or PSP. However, many mutations in other genes have been found to confer a small degree of risk for AD or PSP. Presumably, someone with AD or PSP must harbor at least two such mutations. Now, researchers have created mice with multiple such mutated genes, hoping that they will provide a more faithful mimic of human tauopathy for use in screening drugs before embarking on human treatment trials.
PSP blood test challenges. Tau protein with abnormal attachment of phosphate groups in certain positions is increased in the blood of people with Alzheimer’s disease. This can serve as a diagnostic tool. But the same isn’t true for PSP, unfortunately. This may be because there’s less abnormal tau in the brain in PSP. But in PSP, unlike in AD, the glial cells of the brain have more abnormal tau than the neurons, and a new type of blood test can differentiate between tau from the two brain cell types. This requires measuring tau in tiny, membrane-bound droplets in the blood called “exosomes.” Work to assess the diagnostic potential of exosomes in PSP is ongoing.
PSP as an immune disorder. The tauopathies have been found to involve changes in immune function and the part of the immune system involved is different in the various disorders. In PSP and CBD, for example, the “natural killer” (NK) lymphocytes are more involved, while in Alzheimer’s, it’s more about the microglia. PSP has been found to have a set of gene variants related to glial function and another related to NK lymphocytes that tend to be suppressed to the similar degrees, meaning that the disease may result, in part, from simultaneous insufficiency of these two functions.
Another set of dispatches from the Tau 2022 meeting soon — I promise.