Monthly Archives: November 2023

Putting the cat back into the bag

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Here’s a nice piece of news.

My periodic updates on active PSP neuroprotection treatment trials have mentioned a drug called TPN-101.  That’s an oral drug that inhibits an enzyme called reverse transcriptase.  If that term sounds familiar, it’s because that’s one of the mechanisms of anti-HIV drugs. 

Transposon Therapeutics issued a press release yesterday announcing that a 24-week, Phase 2 trial of TPN-101 in 30 patients showed a reduction of spinal fluid levels of neurofilament light chain (NfL) by 18.4% compared with the 10 patients on placebo.  NfL is a normal protein in brain cells that leaks out into the spinal fluid during active brain degeneration.  TPN-101 also reduced spinal fluid levels of interleukin-6 (IL-6) by 51.6%.  IL-6 is a component of the immune response in the brain that correlates with inflammation, part of the neurodegenerative process in PSP.  There were no important side effects. 

A study of only 30 patients is far too small to show any outward neuroprotective effect that might exist.  This trial was designed to look for chemical evidence of engagement with the “target” cells and proteins in the brain and also to detect major side effects. 

The findings will be presented as a poster at the 18th International Conference on Alzheimer’s and Parkinson’s Diseases in Lisbon in March 2024.

If you’d like to know how this drug works, put on your nerd hat and hang on:  Our genomes are riddled with short stretches of DNA called “transposable nucleotide elements” inserted there by a viruses infecting ancestors hundreds of millions of years ago.  But we have ways to prevent this viral DNA from being translated into proteins.  One protective mechanism, called “chromatin packing,” uses a variety of proteins to surround our DNA strands like insulation on a copper wire, preventing our protein-making machinery from gaining access.  The chromatin, however, does have to grant access to allow normal protein manufacture, and as we age, the chromatin starts to grant too much access.  The old viral DNA can now be encoded into RNA, which our immune system promptly recognizes as foreign.  The result is an inflammatory immune response that, via a variety of pathways, encourages the tau protein to misfold and aggregate.  Those, of course, are the hallmarks of PSP and a couple of dozen other “tauopathies.”  TPN-101 inhibits an enzyme called “LINE1 reverse transcriptase,” which is necessary for the transcription of the transposable nucleotide elements into RNA but is not involved on normal cell processes. In other words, the drug puts that cat back into its bag.

I hope and assume that the next step will be a larger study attempting to show clinical benefit in slowing progression of PSP.  This typically takes months to organize, months more to recruit all the patients, 12 months for the last-recruited patient to complete the double-blind phase, and another few months to analyze.  That totals about 3 years, but at least things are moving in the right direction.

Another four-poster

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Four more poster presentations from the PSP/CBD conference in London in October. Keep in mind that this work has not yet been peer-reviewed by a journal. It has merely been screened by CurePSP and the PSP Association of the UK.

  • “Strategy adherence” is a measure of the degree to which one is consistent in going about a complicated cognitive pen-and-paper task.  Researchers administered the measure every 3 months for a year to people with PSP or PD and also to healthy controls of similar ages.  Each visit also included two more conventional cognitive measures – the Mini Mental Status Exam and the Montreal Cognitive Assessment.  Over the year, they found — in PSP but not in PD nor controls –a very clear and progressive problem with strategy adherence, but not in the conventional tests.  This provides a statistically sensitive test by which to assess disease-slowing ability of experimental drugs for PSP. (Maksymilian Brzezicki, et al, Oxford University, UK)
  • A new gene contributing modestly to the cause of PSP has been found.  It’s called C4A and is involved in the complement cascade, an important part of the immune system.  Ten other genes had been previously found to contribute similarly modest degrees of causation to PSP.  One additional gene influences PSP onset age.  Even if the effects of all 10 causative genes are totaled, most of the cause of PSP remains unexplained.  The current leading theory is that some outside influence is also necessary.  In fact, it may take multiple genes from this list plus multiple outside factors – plus a dose of randomness. (Kurt Farrell, et al, Icahn School of Medicine at Mt. Sinai, New York, NY)
  • Neurofilament light chain (NfL) is a protein in spinal fluid and blood that is elevated in PSP and several other brain degenerations.  Its role as a diagnostic test for PSP remains uncertain, but it does seem to correlate well with rate of symptom progression.  In this report, patients with PSP-Richardson’s syndrome, a rapidly-progressing form of PSP, had higher NfL levels in spinal fluid but only borderline-higher levels in blood, relative to patients with more slowly progressing forms of the disease.  Furthermore, the correlation between spinal fluid and blood levels was only modest.  The conclusion is that levels of NfL in spinal fluid, but so far not in blood, could prove valuable as a prognostic test in PSP. (M. Fernandez, et al University of Barcelona, Spain)
  • The PSP Rating Scale (PSPRS) is nearly universally used as the primary outcome measure in clinical treatment trials.  It progresses in a statistically reliable way over a 1-year timespan,but has been criticized for relying in large part on the neurological exam rather than mostly on patient-reported symptoms.  The PSP Quality of Life Scale (PSP-QoL), on the other hand, relies entirely on patient/caregiver-reported data but has been found in the past not to progress in a sufficiently robust fashion.  Now, researchers have directly compared the two using data from a 124-week, completed, negative drug trial. They found only a modest but still statistically significant correlation between the two, with a correlation coefficient of 0.325 (perfect correlation is 1.0) and conclude that the PSP QoL could provide an adequate outcome measure for PSP trials in the future if this result is confirmed. (Jay Iyer, et al, Harvard Medical School)

Another Fab Four from England

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Yet another, and not my last, installment of research reports from Neuro 2023, the PSP and CBD International Research Symposium held a month ago in London. Please note that many of these reports have not yet been peer-reviewed at a journal.

:: A review of speech therapy records compared various devices to improve communication in people with PSP with severe speech deficits.  In 37 patients, the most successful were large print for reading and a stylus or keyguard (photo) for typing.  As the combination of deficits in motor, cognitive and eye movement control progressed, even these methods lost most of their initial utility.  This study demonstrates the need for better devices to assist in communication by those with advanced PSP.  (CML Foy et al, Sussex Community NHS Foundation Trust, North Chailey, East Sussex, UK)

:: As you’re all aware, two similar anti-tau monoclonal antibodies tested a few years ago failed to slow PSP progression.  However, the trials provided valuable data on the course of the disease over a 12-month period for the middle-stage patients with PSP-Richardson’s syndrome whom the trials enrolled.  The most recent such analysis of the trial for AbbVie’s tilavonemab showed that the patients with greatest language deficits were the ones who progressed most quickly over the ensuing year.  The study measured language in a variety of ways, including naming pictures, following written instructions, writing a dictated sentence, and quickly generating words of a specified category. These results could be of use in understanding the mode of disease spread in PSP, in designing future disease-slowing trials and in counseling patients in routine care. (Indira García-Cordero, et al, University of Toronto, Canada)   

:: A study compared the ongoing production (technically called “expression”) of tau molecules in neurons and glial cells in autopsied PSP brain tissue, correlating the results with the presence of tau aggregates, the pathologic hallmark of PSP.  It found continued tau production in cells with existing tau aggregates.  In fact, in oligodendroglia, where the PSP process probably starts, production was greatest in those cells with the most aggregates.  These findings argue against the theory that existing tau aggregates exert their toxic effect by shutting down normal tau production.  Another conclusion is that the abnormal tau in oligodendroglia doesn’t just come from adjacent neurons, but also (or exclusively) from within the oligos themselves. The results have implications for design of new PSP-slowing drugs. (Shelley Forrest et al, Macquarie University, Sydney, Australia; and University of Toronto, Canada)

:: The Pharma company Amylyx has announced details of their upcoming trial of AMX0035, an orally administered combination of sodium phenylbutyrate and taurursodiol.  It has already shown modest success in ALS in slowing symptom progression and in Alzheimer’s disease at the level of spinal fluid chemistry.  The 600-patient trial in PSP is scheduled to start in December 2023 in 200 centers in Europe, Japan and North America.  The benefit will be measured by comparing the placebo and active-drug groups with regard to rate of progression in the PSP Rating Scale over a one-year period.  Amylyx has not yet posted contact information for prospective participants.   (Disclosure, I’m a consultant for Amylyx and one of the 16 authors of this presentation at Neuro 2023.  The lead author is Günter Höglinger, Ludwig Maximilian University, Munich, Germany.)