A conspiracy theory

In August 2022, over 2 months ago, the august journal Science published an important paper on the genetics of PSP.  I had difficulty wrapping my head around the complicated, cutting-edge technical aspects of the work, so I procrastinated in relaying it to you. 

But last week, at CurePSP’s annual International Scientific Symposium in New York City, the paper’s senior author, Daniel Geschwind of UCLA, presented the work clearly enough for a non-lab person like myself and I now feel comfortable telling you that this paper is a real game-changer for PSP.  The first author is a very junior member of Dr. Geschwind’s lab, Yonatan Cooper, a recent PhD who’s studying for his MD.  The name of the paper is “Functional regulatory variants implicate distinct transcriptional networks in dementia.”

Until now, pretty much all we’ve known about the molecular genetics of PSP is that there are two places in MAPT (the gene encoding the tau protein), where one version of the gene is a little more common in people with PSP than in healthy people, and that there’s similar incrimination of a handful of other genes on other chromosomes.  These variants are all in “markers,” rather than in the genes themselves.  That is, a spot near the gene is the thing whose variant is statistically over-represented in those with the disease relative to healthy people.  That doesn’t tell us for sure which of the dozens of genes in the vicinity of the marker is the actual disease-associated gene and it definitely doesn’t tell us the nature of the gene’s defect, or how it contributes to brain cell loss.

But now, the researchers at UCLA have analyzed the actual function of the genes in the chromosomal neighborhood of each of 9 markers associated with PSP.  This is a huge undertaking, so they use a new technique called a massively parallel reporter assay (MRPA), which reveals gene expression.  That is, it shows the types and amounts of proteins encoded by each of the 9 PSP-related genes and the other nearby genes incriminated by that marker.

The result was that the PSP-associated genes didn’t encode proteins themselves, but rather, served a regulatory function.  The two genes most heavily associated with PSP were PLEKHM1 and KANSL1.  Both are on chromosome 17, very near the MAPT gene.  The disordered DNA sequences for PSP were transcription factor binding sites, the places in the gene where regulatory proteins can attach in order to do their job of adjusting the amount and composition of the protein encoded by that particular stretch of DNA. 

So, what does this mean?  To quote the paper, “These analyses support a mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk in aggregate through polygenic cell type-specific regulatory effects on specific gene networks.”  The English-language version is that they showed that the genetic contribution to PSP consists of variants in members of groups of genes that work together to regulate a specific cellular function.  An individual with PSP simply has the bad luck to harbor enough such genes to get the disease process going. 

The research paper shows that the gene variants themselves don’t directly encode a toxic version of a normal protein, as occurs in Huntington’s disease or other highly heritable brain degenerations.  The toxic levels of tau in PSP must therefore be the indirect result of the disordered gene regulation, and as Dr. Geschwind emphasized, this and many other possible indirect effects of genetic variation contributing to the cause(s) of PSP remain to be discovered. 

The fact that multiple genes must conspire together to produce the disease could explain why PSP is almost never familial: it’s very rare that more than one member of a family would have enough of the gene variants to accomplish any nefarious purpose.  Someone with PSP would have had to inherit some variants from Mom and some from Dad, neither of whom had enough variants to cause the disease in themselves.  Then, of course, one or more environmental exposures or experiences are probably also necessary but insufficient co-conspirators.  But that wasn’t part of this project.

Enough for now.  In a future post I’ll speculate with abandon on the implications for anti-PSP drug development.

Current clinical trials

As always, at your service.

Here’s an updated list of current and possible future clinical trials that I know of for PSP. For more information, visit www.clinicaltrials.gov and in the search box, enter the ID number in the first column. If you’re interested in joining an observational study (i.e., one not involving treatment), those are listed on the website as well.

clinicaltrials. gov IDDrugSponsorPhaseMechanismLocation(s)DosingComments
noneSodium selenateGov’t of Australia2Enhances dephosphoryl-ation of tau by protein phosphatase 26 sites in AustraliaOralRecruiting
NCT 04734379FasudilWoolsey2aRho kinase inhibitorUCSFOralCompleted recruiting; Study to end in 11/2023.
NCT 04993768TPN-101Transposon2aReduces tau productionBoca Raton, FL, Farmington Hills, MI, Las Vegas, NV, Gainesville, FL, Englewood, COOral30 patients on drug, 10 on placebo; completed recruiting; completion 7/2023
NCT 04937530RT001 (di-deuterated linoleic acid ester)BioJiva (product from Retrotope)2aReduces lipid peroxidation, enhancing mitochondrial activityUniversity of Munich (Germany)OralNon-controlled study showed very slow PSP progression over 2 years.  Small RCT results due in 11/2022.
NCT 04539041NIO-752Novartis1Anti-sense oligonucleotide; reduces tau productionRochester MN, Nashville TN, La Jolla CA, Boca Raton FL; 2 in Montreal; 5 in Germany; 1 in UKInfusion into spinal fluid at lumbar spaceStill recruiting; 4 injections into spinal space over 3 months. Completion in 5/2024.
NCT 04008355AZP2006AlzProtect1Reduces phosphor-tau by enhancing progranulin3 sites in FranceOral solution~24 patients on drug, `12 on placebo
noneAtomoxetine (brand: Strattera)Cambridge University2aFor mood disorders of PSPCambridge, UKOralNoradrenaline for Progressive Supranuclear Palsy Syndromes (NORAPS).  Contact james.rowe@mrc-cbu.cam.ac.uk
NCT 04468932TMS in PSPOregon Health & Science U, Portland; NIHNATranscranial magnetic stimulationPortland, ORNon-invasive magnetic fieldRecruiting; Expected completion: June 2026
NCT 04014387Suvorexant and zolpidemUniv of California, San Francisco4Two approved sleep aids never before evaluated in PSPAll evaluations are remoteOralCompletion expected May 2024. No need for patient to travel to research center. The expected benefit is in sleep, not movement.
NCT 03924414Zoledronic acidCalifornia Pacific Medical Center Research Institute4Anti-osteoporosis drug to prevent fractures in neurological diseases with falling55 locations, all in the USOne intravenous infusionCompletion expected Nov 2023.
May start recruiting in the next year: 
?ASN120290Asceneuron1Reduces tau misfolding and aggregation by inhibiting O-GlcNAcase? Press release info only
?MP201Mitochon1Mitochondrial decoupler? Early in planning per press release
?Tolfenamic acidNeuroTau2NSAID that reduces tau productionCleveland Clinic, Las Vegas + others?  

We can dream, can’t we?: An unscientific survey

Here’s a hypothetical question for you all:  How effective does a neuroprotective drug have to be for you to want to use it?

What prompted this question is the recent FDA approval of a new drug to slow the progression of ALS (Lou Gehrig disease).  It gives the patient, on average, 25% more survival time.  Now, suppose a drug to slow the progression of PSP provided the same benefit?

The average person with PSP received the correct diagnosis about 3½ years after the first symptoms appear and, with currently available treatment, die an average of 4 years later.  So if a new drug slowed the progression by 25% and is started immediately after the diagnosis of PSP is made, then that 4 years becomes 5 years – not much of an improvement, but better than nothing.

The cost of Relyvrio for ALS is $158,000 per year.  The cost of Aduhelm, which was approved last year for slowing the progression of Alzheimer’s disease, is $28,000.  Let’s say our hypothetical PSP drug splits this difference, at $93,000.  We don’t know how much of that would be covered by the various drug insurance plans, and of course, not everyone has drug insurance. 

Let’s assume that the hypothetical PSP drug has no important side effects and that it requires a monthly intravenous infusion lasting 2 or 3 hours.  (Some of the experimental PSP drugs are just oral pills and one is an injection every 3 months into the spinal fluid, as for a spinal tap.)

So, my question boils down to this:  Would you opt to receive this PSP drug with a 25% slowing benefit – or not?  The benefit to the average patient would be one more year of survival – more for some, less for others. 

A point in favor: The drug wouldn’t just prolong the final year, when the person is most disabled.  Rather, it would prolong each year of those 4, so that the first year’s mild level of disability would persist for 15 months rather than 12, and so on.

Two points against: 1) You’d have to take the drug for the rest of your life, or until something better came along. 2) Future participation in a clinical trial of a potentially better drug might not be allowed for people already on another PSP-protective drug.

Any thoughts for my highly unscientific survey would be appreciated.  Click “Leave a comment” just below this line.  Feel free to explain your thinking.

Genetic testing advice

I’ll plagiarize myself again. CurePSP asked me to write up a piece in response to someone asking if a person with PSP or CBD (or suspected PSP or CBD) should have genetic testing. The short answer is mostly “no,” but here are the details:

People with an established diagnosis of PSP or CBD and a close relative with one of those conditions (or a strong suspicion thereof) should consider having their MAPT gene sequenced.  That’s the gene encoding the tau protein.  But the vast majority of those with PSP or CBD have no similarly affected relatives, and for them, genetic testing is neither necessary nor useful.

The test should sequence the entire MAPT gene and not merely check for the ten mutations, all of them very rare, that have been associated with PSP (seven with CBD) in the past.  If the person with the disorder (called the “proband”) proves to have a mutation in MAPT, then other family members with similar symptoms can be tested as well. 

Variants in eight genes other than MAPT have been associated with PSP and five with CBD, but each of these raises the disease risk only slightly and testing for them is not useful in an individual or even in a family.  That’s because these are only “marker associations,” not specific mutations altering a protein known to be involved in the PSP process. The markers are called “single-nucleotide polymorphisms” or “snips” and unlike the MAPT mutations, they incriminate a span of about 100 or so genes, not a specific gene, much less a specific mutation that can be tested for.

We must keep in mind that many mutations, even in genes like MAPT, are harmless and do not cause disease.  Sixty MAPT mutations have been reported in humans so far, and only ten of them are known to cause PSP. So having a mutation in MAPT and having PSP doesn’t necessarily mean that one caused the other.  If a relative with the same symptoms has the same mutation, it may still not be cause-and-effect, but if that relative is distant, or the proband and two or more relatives share symptoms and a mutation, then the likelihood of cause-and-effect is greater. 

Even if there’s a good statistical likelihood that the proband’s mutation is the cause of their disease, and a healthy relative proves to have the same mutation, one still would not be able to predict how soon the relative might start to develop symptoms.  That information could be available soon from some other type of “pre-symptomatic” or “predictive” testing, but no such test has yet proven to be sufficiently accurate in such a situation.

People with suspected PSP or CBD with no relatives with similar symptoms have no need for genetic testing.  Even if one of the known PSP/CBD-causing mutations were found, it would not contribute much to the likelihood of PSP or CBD as the diagnosis explaining the symptoms.  The same is true for the healthy relatives of someone with established PSP/CBD.

So, as you can tell, estimating disease risk from genetic testing can be complicated.  That’s why a professional genetics counselor or a physician with expertise in adult neurogenetics should advise anyone considering having family genetic testing for PSP or CBD. Don’t just rely on the simple report supplied by 23andMe.

I’ll update this as necessary.

Let’s talk about paw-paw.

Rousting me out of my recent blog-post drought was some click-bait I saw about the growing popularity of a fruit called paw-paw.

The paw-paw fruit with its seeds

So-named because of its outward resemblance to papaya, paw-paw grows on trees both wild and cultivated, in the eastern US and Canada.  The flesh is sweet and creamy, like a banana, and can be consumed in many forms.  Maybe the only reason it’s not more popular is that the fruit is easily bruised during shipping.  It’s one of the faves of the locavore, farm-to-table movement in eastern North America.  So, what’s not to like?

Here’s what: Paw paw contains a mitochondrial toxin called “annonacin.”  It’s not only on the seeds, leaves and roots, where toxins exist in many plants with harmless fruit, but also in the fruit itself.  The toxin inhibits the action of “complex I,” a critical part of the process in the mitochondria that makes energy from sugars and oxygen.  It seems likely that the toxin serves the plant as a defense against insects, whose mitochondria, like ours, are susceptible to it.

Annonacin first reached the attention of scientists studying neurodegeneration after the 2002 publication of a description of a tauopathy endemic on the Caribbean island of Guadeloupe.  A third of the people with that disease met diagnostic criteria for PSP. The others had falling, frontal cognitive loss and disinhibited emotional responses, but not the eye movement palsy of PSP.  Compared with people on Guadeloupe with typical Parkinson’s disease or healthy controls, those with “Guadeloupean tauopathy,” as it came to be called, were far more likely to have consumed a tropical fruit called soursop. You guessed it: soursop turns out to have harbor annonacin, like paw-paw.

Prompted by that information, scientists in Germany injected annonacin intravenously into rats.    The result was a tauopathy that resembled PSP in the rats’ motor behavior and in the appearance of their brain cells under the microscope. The same group subsequently found that annonacin can cause tauopathy by a very different mechanism as well.

Shortly thereafter, I did a dietary risk factor survey among my patients with PSP, comparing them to controls with non-degenerative neurological diseases from our clinic.  So few had ever eaten paw-paw (or soursop) that the study didn’t have the statistical power to answer the question and I never published it.  (The more common foods included in the questionnaire gave no statistically significant results, either, in case you were wondering.)

Bottom line: There’s probably not enough annonacin in paw-paw to cause PSP or other tauopathies after only occasional consumption.  But over decades?  And what about people with a genetic predisposition to develop tauopathy?  Or people who just love paw-paw and eat them like candy? (There are some!) I think more research and some careful thinking by the FDA is needed before paw-paw becomes more widely marketed and consumed alongside apples, bananas and oranges.

Lecanemab for Alzheimer’s: “Proof of Principle” for PSP

I’m not above plagiarizing myself. What follows is a piece I just wrote for the CurePSP website. It’s pitched at a simpler level than most of my blog posts, but it’s close enough. As I learn more about this drug, I’ll fill in some technical details for you.

Great news for people with Alzheimer’s disease:  A monoclonal antibody for intravenous infusion called “lecanemab” has been found to slow the rate of worsening of early-stage AD by 27%.  The Japanese drug company Eisai, which developed the drug, and the US company Biogen, which is assisting in the testing, jointly announced the news on September 26.  If approved by the FDA, lecanemab would be the first drug available to slow the underlying disease progression in AD rather than merely treating the symptoms, as Aricept and other existing drugs for AD do.

In almost all neurodegenerative diseases, one or more proteins forms clumps called “aggregates” in brain cells.  Lecanemab is an antibody directed against beta-amyloid, which is one of the two proteins that aggregate in AD.  The other such protein is tau, which of course is the one protein that aggregates in PSP and CBD.  In MSA, the protein is alpha-synuclein.  Beta-amyloid protein is not involved in PSP, CBD or MSA.  Two different monoclonal antibodies directed against the tau protein have failed to slow progression in PSP.  Nevertheless, the lecanemab news is welcome for people with PSP, CBD and MSA.  Here’s why:

  • This is the first demonstration that reducing levels of the aggregating protein in a neurodegenerative disease can actually slow the ongoing progression of the condition in humans.  (This has been accomplished in many ways in lab animals, but their artificial versions of human brain diseases are very incomplete models.)  This means that some other way of reducing tau protein in humans with PSP/CBD might work.
  • The two monoclonal antibodies that have failed in PSP were directed against the same end of the tau protein (called the “C-terminal” or “microtubule-binding domain,” if you want to get technical).  Other monoclonal antibodies directed against the other end of tau (the “N-terminal”) might work better, especially as fragments of tau that include the N-terminal now seem to be the bad actors.  Such monoclonal antibodies are in early-phase testing.
  • Until now, it has not been fully clear that in human neurodegenerative diseases, the aggregating protein is what’s causing the loss of brain cells.  Competing theories suggest that something else is damaging the brain cells and the protein aggregation is merely a result of that process rather than its cause.  The lecanemab news suggests that the aggregates themselves are to blame.  This makes future drug development a lot easier and more focused.
  • Although no monoclonal antibody trials are currently in progress for PSP, CBD or MSA, there is a current trial of another way to reduce tau protein.  Rather than destroying protein as antibodies do, this approach prevents the offending protein from being manufactured in the first place.  It’s called “anti-sense oligonucleotide” treatment, and an early-phase safety trial for PSP is under way at several sites in the US and elsewhere.  Trials of other ASOs for other neurodegenerative diseases are planned.

So, we congratulate the AD world on this successful trial, which we hope and expect will be the first of many, and we take heart that this “proof of principle,” as scientists call it, can soon be applied to PSP, CBD and MSA.

More fun than a spinal tap

A diagnostic tool routinely used in psychology is the Rey-Osterreith Complex Figure:

Diagram, shape, engineering drawing, polygon

Description automatically generated

The patient is timed while copying the figure.  The figure and copy are removed and the patient re-copies the figure from memory immediately and again after 30 minutes.  It’s a sensitive measure of visuospatial recall, visuospatial recognition, response bias, processing speed, and visuospatial constructional ability.

Although the test has existed in its current form since 1944, there has been no publication on its utility in PSP.  Now, an Italian research group at the University of Pisa led by Dr. Luca Tommasini gave the test to 30 people with PSP-Richardson syndrome, 30 with Parkinson’s disease and 30 healthy persons matched to the others on age, gender and educational attainment. 

It was previously known that people with Parkinson’s make errors on the test related to planning and impulsivity.  The new study found that in PSP, those errors are more severe than in Parkinson’s, with the added problems of disinhibited repetition of some elements and “vertical expansion” of the figure.  The latter could be related to the difficulty in moving the eyes vertically or to an underlying difficulty in accurately conceptualizing vertical space.  In my own experience with people with PSP, there is disproportionate difficulty attending to objects and events at the upper and lower extremes of the visual space even if the eyes were still able to move adequately in those directions.

These results could help distinguish PSP-RS from PD diagnostically.  We await results for the other disorders with which PSP can be confused such as multiple system atrophy-parkinsonism and corticobasal degeneration.  We also await results from very early-stages of the disease, when such a diagnostic test would be most useful, and from variant forms of PSP such as PSP-parkinsonism and PSP-progressive gait freezing, where cognitive abilities are not usually as impaired as in PSP-Richardson syndrome.

Anti-sense oligo update

CurePSP asked me to write up something on ASOs for their website (www.curepsp.org). Thought I’d give my loyal blog readers a sneak peak:

Probably the single biggest story in the world of PSP right now is NIO752.  That’s an antisense oligonucleotide (ASO) being tested for safety and tolerability in people with PSP.

ASOs interrupt the process by which a specific gene’s DNA is transcribed into RNA, thereby reducing the production of the encoded offending protein.  The ASO itself is a short stretch of RNA whose genetic code is a mirror-image of part of the DNA whose translation is to be suppressed.  The ASO’s genetic sequence and that of the offending DNA recognize each other and stick together, preventing the corresponding protein from being produced. In this case, the targeted DNA is the MAPT gene, which encodes the tau protein. Other ASOs operate by targeting slightly different stages of the transcription/translation process.

In the US, the FDA has approved several kinds of ASO, the best-known being nusinersin (brand name “Spinraza”) for spinal muscular atrophy, a progressive and usually fatal condition that typically starts in infancy but in mild forms can start at any age.  In the pivotal trial of nusinersen, 21 of 51 infants receiving the drug were improved after 6 months, while that was true for none of the 27 infants receiving sham treatment.  If we can achieve similar results for NIO752, it would be by far the best news ever for PSP.

ASO molecules are too large to cross the blood-brain barrier, which means that for a brain disease, they must be administered by injection directly into the spinal fluid.  This is performed as for a diagnostic spinal tap.  In the current trial, NIO752 is given once monthly over a period of 3 months and the participants are examined periodically for an additional 9 months.  The 64 participants are at 4 sites in the US (La Jolla, CA; Boca Raton, FL; Rochester, MN and Nashville TN), 2 in Canada (both in Montreal), 5 in Germany and 1 in the UK. This safety and tolerability trial is expected to end in May 2024.  Its sponsor is Novartis Pharmaceuticals, co-headquartered in Basel, Switzerland and Cambridge, MA. For more information: 1-888-669-6682 or novartis.email@novartis.com

A trial can detect important safety issues with only 64 participants but detecting actual benefit requires more.  The standard “primary outcome measure” for clinical treatment trials in PSP is the PSP Rating Scale.  Assuming that is still the case in 2024, when a treatment trial would begin, and half of the participants receive placebo, the minimum number of participants needed would be 276.  That number also assumes that the study is designed to detect at least a 30% difference between the two groups’ rates of progression.  Detecting less of a difference would require more participants and detecting a greater difference would require fewer.  A new outcome measure with less variability than the PSPRS would reduce the number of participants required.

From the standpoint of those with PSP and their families hoping to enter a trial of NIO752, the most important number isn’t a number, but a date: A trial starting in mid-2024 would probably end in 2027. Another important number is the eventual price of the drug.  NIO752 would have to be injected every month, lifelong. Nusinersen’s price is $125,000 per injection.  So, if the price of NIO752 is anything like that, the cost to Medicare, Medicaid and private insurors would present an impossible situation.  CurePSP estimates that about 20,000 people in the US have PSP at any given time.  If even half of them received a $125,000-per-month drug, the total annual cost would be $15 billion plus the doctors’ fees for the monthly injection procedure.  Clearly, something would have to give. 

But first, let’s hope that NIO752 actually works.

Executive dysfunction, as it were

A major announcement: There’s now evidence that an important factor in the cause of PSP are variants in two “regulatory genes” called PLEKHM1 and KANSL1, both of which are very near the MAPT (tau) gene on chromosome 17. 

Regulatory genes are not encoded into protein.  Rather, they affect the rate at which other genes are transcribed into protein, kind of like business executives or military officers directing the activities of others.  Such proteins are called “transcription factors.” The project identified the gene being regulated in this case as SP1, which encodes the protein called Sp1 (note the lowercase p; the fewer abbreviations in science, the better, I always say). SP1 is located on chromosome 12 and works in tandem with a group of other genes to regulate many cellular processes. 

As a comparator, the researchers used samples from people with Alzheimer’s disease, finding that it involved a different set of regulatory genes that did not interact with SP1.  This result could allow drugs that regulate the Sp1 protein or gene-directed therapy for the PLEKHM1 or KANSL1 genes to be developed as treatment or prevention for PSP. The new finding’s significance is underscored by its publication in Science, one of a small handful of top general scientific journals. 

The research was a collaboration between the highly productive neurodegenerative genetics groups at UCLA and UCSF, with Drs. Daniel Geschwind and Martin Kampmann, respectively, as senior members.  The first author was Yonatan Cooper, an MD/PhD student at UCLA.  In response to my email, Yonatan commented, “A key challenge in modern medicine has been interpreting genetic risk factors [for diseases of complex causation] and translating them to understand disease mechanisms. This is especially true for the 17q tau locus, which is the major genetic risk factor for PSP.  The approach that we used was crucial to allowing us to identify these new genes in that region.” 

The “approach that we used” in Yonatan’s quote is called a “massively parallel reporter assay” (MRPA).  It assesses thousands of single-nucleotide DNA variants for their ability to regulate other genes’ protein expression levels.  For this study, the researchers chose the region close to the two variants in or near the MAPT gene found in 2011 by the PSP Genetics Consortium and funded by CurePSP.  That region comprises hundreds of genes, any of which could be actual source(s) of the PSP risk in that region of the genome.

That 2011 study used “single-nucleotide polymorphisms (SNPs)” in DNA from autopsy-confirmed PSP brain tissue and control subjects.  Even now, 11 years later it remains the most informative single study on the genetics of PSP.  (Disclosure: I was a minor co-author.)  It identified a handful of regions across the genome where a marker differs between the two groups, implying that a gene near each marker contributes to the cause of PSP.  Two of those markers were in or near MAPT.  But that technique can’t positively incriminate which of the hundreds of genes in that region of chromosome 17 actually cause(s) the disease.  The current study did that by testing all of the thousands of variants in those genes for their ability to alter protein production in a way that could help cause PSP. 

One next step is to look for drugs or other treatments to counter the effect of these two regulatory abnormalities on the function of the SP1 protein and/or a protein with which it interacts.  Another next step is to use the same technique to look for other regulatory genes near the other PSP-related markers identified in the 2011 SNP study and more recently and to look for drug targets in the protein products of the genes they regulate.

I don’t know about you, but I’m nerdy enough to be very excited about this!

Thinking out loud

I’m making a list of clinical topics to be covered in CurePSP’s next annual scientific conference.  That task made me think carefully about what’s important to clinicians seeking to stay current on PSP and CBD.  So, I thought I’d share that list with you all, for what it’s worth.  Keep in mind that the laboratory research end of things will be a separate list.

  • Clinical spectrum and its pathology
  • Clinical aspects of genetics and epigenetics
  • Fluid biomarkers             
  • PET biomarkers
  • MRI biomarkers
  • Clinical outcome measures (rating scales, wearables, eye movement, gait measures, etc)
  • Gene therapy
  • Tau-directed drug trials
  • Mitochondria-directed drug trials
  • Gait retraining
  • Current best practices in symptomatic care