Monthly Archives: January 2024

. . . and we have liftoff

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The first of a raft of experimental PSP drugs in the pipeline has begun enrollment in a large treatment trial.

The ORION trial (don’t ask me what the acronym stands for) is sponsored by Amylyx Pharmaceuticals.  Their press release is here. A bit more information is at the company’s website. Their email address is clinicaltrials@amylyx.com.

Clinicaltrials.gov lists more info, including a phone number (in the UK):  +44 (808) 1642604. Only a few of the planned 33 sites in the US are open so far and no sites outside of the US has yet opened, to my knowledge. Those will be in Europe, Canada and Japan.

The product is actually two drugs called taurursodiol and sodium phenylbutyrate.  They have a variety of beneficial actions in brain cells affected by PSP, but it’s not known which would be most important.  Both drugs are already on the market, the first over-the-counter and the second with prescription.  Neither alone is intended for brain diseases and each alone has only a minimal effect on the brain.  But the two together have a synergistic effect on the brain and spinal cord that has proven modestly beneficial in ALS and has already received FDA approval for that disorder under the brand name Relyvrio.

There’s a lot more you’d want to know about the study’s design and the participants’ obligations, so please read the material at the links I’ve provided above and contact the company directly. 

Amylyx has hired a contract research organization called Cronos to actually run the trial.  They’re a subsidiary of a company called IQVIA.  So if you encounter those names, no worries.

One more little thing: full disclosure. I’m a paid consultant for Amylyx, but that’s only for advice in the design of the trial and instructing the examining doctors how to use the PSP Rating Scale. They don’t pay me to recruit patients and my fee does not depend on the trial’s enrollment. Nor do I own stock in the company or have any other financial incentive to see the drug succeed. (Of course, I do have an emotional incentive for that — no secret there.)

Seek and ye shall find

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This week, our knowledge of the genetics of PSP has more than doubled.  First, as usual, some background:

Like many other complex conditions like atherosclerosis, schizophrenia and most cancers, PSP does run in families a bit more often than expected by chance.  But as in those diseases, the familial tendency is too weak to produce the classic dominant or recessive pattern associated with a single, strongly-acting gene variant as in Huntington’s, Tay-Sachs or sickle cell anemia. Besides, adding up the risks from the known PSP-related genes wouldn’t explain the incidence of the disease in the population, rare though it is.  That has prompted the theory that some unidentified external exposure or experience also has to play a role. 

Over the past 25 years or so, a number of gene variants have been found to confer slight risks for developing PSP.  The first-discovered and still the most important, called the “H1 haplotype,” is a complex set of variants in region of chromosome 17 that includes MAPT, the gene encoding the tau protein. Another four variants on other chromosomes were published in 2011 by CurePSP’s PSP Genetics Consortium. 

In the years since, nine other variants were added piecemeal by other researchers. Those first 14 were all discovered using a technique called “marker association,” which only identifies a region of about 100 genes where the culprit gene would be located.  The gene from those 100 that’s reported as a “hit” is generally the one with the best statistical association with the marker along with a scientifically rational reason to be associated with the disease under study.  A more finely-grained search would actually work out the sequence of the genetic code, comparing people with PSP to those without PSP.  That wasn’t practical back in 2011, but now it is.  It’s called “whole-genome sequencing” or WGS.

The new list of gene variants has been found by an international WGS collaboration that grew out of the original CurePSP-supported team.  They used DNA samples from 1,718 people with PSP, of whom 1,441 were autopsy-confirmed, and 2,944 samples from people without PSP as controls.  The leaders are at the University of Pennsylvania and UCLA, but 26 other research institutions in nine countries contributed.

They confirmed five of the six previously-identified variants (the sixth came very close) and added seven new ones. They also elucidated new details of the cluster of variants in the H1 region.  Most remarkably, they confirmed a previous, smaller study showing that PSP reverses the relationship of Alzheimer’s disease with the ApoE gene on chromosome 19.  In AD, the epsilon 4 variant of ApoE is over-represented relative to controls and the epsilon-2 variant is under-represented, while in PSP, it turns out that those proportions are reversed despite the fact that both AD and PSP are tauopathies.

So far, the research article is only posted on medRxiv (“med archive”), a website for manuscripts not yet through the peer review process at a journal.  (But my brain’s blogging center couldn’t restrain itself.)  The next steps for the authorship team are to gather online comments on the manuscript from other scientists and to submit the resulting revision to a regular journal.  There, the peer review may dictate other changes.  The next scientific step will be to figure out what the mutations are doing wrong, determine to what extent the variants increase or decrease the amount of the protein they encode (called “expression studies”), and look for proteins encoded by those genes (or for proteins they interact with) that might be modulated by drugs.

As far as I can tell, even the newly expanded list of risk variants doesn’t explain enough of the overall cause of PSP to be used as a diagnostic panel.  But it’s a start in that direction.

My canned lecture on PSP includes a slide on the two dozen or so most important scientific milestones in PSP research since the disease was first described in 1963.  This paper is going there.  As I learn more about the publication progress and clinical implications of this work, I’ll keep you all apprised.

Seeds of a revolution?

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Decades ago, the discovery that specific proteins aggregated in the brain cells of specific neurodegenerative diseases was a major advance.  But like so many other scientific breakthroughs, it created another question: Why are there so many different clinical pictures among different people with the same neurodegenerative disease (like PSP) despite the fact that they all host the same aggregating protein (in this case, tau)? The ability of abnormal tau to “seed” the disease process into previously healthy brain areas is at the root of the disease process, but we’ve had scant clue as to how that works, exactly.

For PSP, the most important clinical variable is the eight subtypes (PSP-Richardson’s syndrome vs PSP-Parkinsonism vs PSP-progressive gait freezing, etc), and slightly less variable features are the onset age and rate of progression.  In the past year or two, it’s become clear that the different subtypes tend to emphasize different areas of the brain, but that doesn’t explain why two people with the same subtype can have different onset ages and rates of progression.

This mystery became even more mysterious recently when a new electron microscopy technique called “cryo-EM” proved able to visualize individual protein molecules. It showed that for everyone with a given disease, the protein for that disease had the same misfolded shape.  In other words, the tau molecule assumes the same rigid squiggle in everyone with PSP, a different rigid squiggle in everyone with Alzheimer’s, yet another in everyone with corticobasal degeneration, and so on.  But that raised the question as to the reason for the variability among patients of the PSP onset age and rate of progression.

Now, researchers at the University of Toronto’s Rossy Centre, an institution dedicated solely to PSP research at the , have found new evidence supporting the old idea that the key may be in the “oligomers” or “high-molecular weight tau” or “HMW tau.”  These are stacks of tau protein molecules small enough to remain dissolved in the brain’s fluids, as opposed to single molecules or the large, insoluble neurofibrillary tangles visible through a conventional microscope. 

The top-line result was that the patients with more rapidly-progressive PSP and brain regions with the worst damage had higher levels of HMW tau.  In a tour-de-force of lab experiments, the Toronto researchers also showed that:

  • HMW tau was more resistant to the brain’s mechanism for breaking down such protein clusters.
  • The study’s 25 PSP patients could be divided into high-, medium- and low-seeders based on the speed with which their tau converted healthy tau to their own misfolded form.
  • Tau with phosphate groups attached to amino acids 202 and 205 were least likely to form the HMW tau clusters.
  • The pattern of production of proteins (i.e., the “proteomics”) in the brain areas rich in HMW tau showed disruption of the brain’s adaptive immune system and two other cellular systems previously known to be related to neurodegeneration.

The importance of all this is that we now have a more specific idea of the structure of the most toxic form of tau aggregates and that boosting the brain’s adaptive immune system with medication could discourage the seeding of misfolded tau into healthy cells.

The study’s first author, Dr. Ivan Martinez-Valbuena, published an editorial in the journal Brain Pathology explaining all this in language that non-specialist scientists can understand.

The research paper itself is posted by the authors in bioRxiv (“bio-archive”) an on-line, open-access website for articles awaiting word from the peer-review process at a conventional journal. Its senior author is Dr. Gabor Kovacs, one of the world’s leading neuropathologists in the field of neurodegenerative diseases.

It’s awards season

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A caregiver has asked me, as CurePSP’s Chief Clinical Officer, to list the most important clinical research advances in PSP of 2023. Happy to oblige. Here are my top five in no particular order. 

  • The FDA approved a combination of two drugs called taurursodiol and sodium phenylbutyrate with the brand name “Relyvrio” for use in amyotrophic lateral sclerosis (ALS; Lou Gehrig disease).  A trial in PSP has already started to recruit patients.  The drugs address an issue in the mitochondria shared by the two diseases in different sets of neurons.
  • Tau PET ligand APN-1607 received go-ahead from the FDA to proceed to a pivotal Phase 3 trial.  Such a trial began recruitment in December in the US and will involve multiple other countries as well.  The compound would allow a diagnosis of PSP in early or equivocal cases by being taken up by the abnormal tau protein in the brain and imaged.
  • A drug called TPN-101 was found to be safe and well-tolerated in a Phase 1 trial of 30 patients with PSP.  The drug counters inflammation in the brain by reducing the transcription of ancient viral DNA in our genome.  Next is a small trial for efficacy.
  • A simple, remote, gait-monitoring system with only three sensors proved able to distinguish the gaits of PSP and PD.  Further testing for its ability to document progression or improvement will follow.
  • PET imaging of frontal lobe synapses showed good correlation with the PSP Rating Scale and with the results of cognitive testing.  This is different from typical PET in neurodegenerative disease, which images glucose utilization or protein aggregates.  The work suggests that synaptic imaging could be a good diagnostic marker in the earliest, pre-symptomatic stages of PSP.

But the most important piece of news is that several drug companies are planning to start clinical treatment trials in the next year or two. I’ll report on all that as it happens.