A clue from proteomics

The annual conference of the International Parkinson and Movement Disorders Society (“MDS”) is in progress this week on line.  The location of this meeting normally migrates from city to city world-wide and this year was supposed to be Philadelphia.  Nice city to visit – great history, great art, great restaurants (both fancy and ethnic).  Oh, well.  One of our many sacrifices to the pandemic and all things considered, not a serious one.

Of the 1,000 posters reporting new research, 17 were on PSP.  One that sounds very interesting is from Hiroshi Takigawa and colleagues at Tottori University in Yonago, Japan.  They did a proteomic survey of cerebrospinal fluid (CSF) from people with PSP, Parkinson’s, corticobasal syndrome and some healthy, age-matched volunteers.  Proteomics is a generic term for big-data studies of all the proteins in a biological samples, just as genomics is the study of all the genes.  In this case, they compared the collection of thousands of CSF proteins among the four groups listed and found that the only one that’s higher, on average, in PSP relative to the other three to a statistically significant degree is something called chromogranin B.  They also found that a small fragment of the 657-amino acid chromogranin B protein was the only protein (or fragment thereof) that was less abundant in CSF in PSP, on average, than in the other conditions. The fragment, which is only 31 amino acids long, is called bCHGB-6255.

For neither of these findings was the magnitude or consistency of the difference enough for use as a diagnostic test at the individual level.  (Statistical digression: For the biostatisticians among you, the area under the ROC for bCHGB-6255 was only 0.67.  For the rest of you, the receiver operating characteristic is a graph comparing the likelihood of true positives with that of false positives for the full range of possible definitions of an abnormal level.  The area under the ROC, if the each axis of the graph goes up to 1.00, has a theoretical maximum of 1.00, in which case there’s no risk of false positives in exchange for full identification of the true positives.  A result of 0.80 is barely acceptable for a test to be useful at the individual level and 0.90 is preferred.)

The value of the finding is the demonstration that chromogranin B might have something to do with the degenerative process underlying PSP but none of the related diseases.  Furthermore, the inverse relationship of the full chromogranin B molecule and its bCHGB-6255 fragment suggests that there’s something about the fragmentation process that may be uniquely important to PSP.  Maybe an enzyme that cleaves chromogranin B is deficient, damaged or suppressed in PSP.  Only further research will work that out.

What does chromogranin B normally do?  We don’t know.  It’s present in a wide variety of brain cells that use norepinephrine as their neurotransmitter and also in many cells in other organs.  It’s somehow associated with the secretion of norepinephrine and its blood levels are known to be elevated by certain tumors.  Tests for it are available from commercial medical labs.  But as I emphasized above, the test would be diagnostically useless at the individual level.

Most of the presentations at important meetings like the MDS are research that has not yet passed peer review, or at least not yet published.  So you have to take it with a grain of salt.  Of course, the same thing can be said for any research that has not been confirmed by other labs using other methods.  And even then . . . I’ll tell you about other interesting MDS posters in the next few days.

A family matter

Want to know what’s hot in lab research on PSP?  Or, more accurately, want to know what will be hot in a year or two?  This week, CurePSP will announce its four newest research grant awardees.  Most of the 20 competing applications, a very large crop for CurePSP, were of excellent quality and in a less competitive cycle many of them would have been funded.   A fifth and possibly a sixth application may be funded next month after CurePSP’s leaders have had a chance to discuss the use of a new, unexpected, seven-figure donation.

Since I’m driving this bus, I’ll start with the funded grant I consider the most intriguing, though it’s the smallest of the four.  For two decades, researchers at the University of Southern California have been following a Mexican-American family with PSP in 14 members over three generations.  Two of the 14 have had autopsies confirming the diagnosis.  The inheritance pattern is most likely autosomal dominance (look it up).  There are six living, affected members and another 19 who are at 50% risk because they have an affected parent or sibling.  One of the affected members has had sequencing of the gene that encodes tau (called the MAPT gene).  That revealed no mutations.  Now, John M. Ringman, PhD and his USC colleagues plan to sequence the entire genome of four affected and one unaffected family members.

It’s entirely possible that the result will be a mutation in one of the half dozen or so genes besides MAPT that have already been identified by other methods as conferring a slight risk of developing PSP.  That wouldn’t be so exciting, though it would show that one mutation in that gene suffices to cause the disease while other mutation(s) in the same gene only raise PSP risk slightly.  That would shed light on just how that gene works with respect to PSP.

A more exciting result would be if the culprit gene in this family turns out to be one that has not been previously associated with PSP.  Even though this particular mutation would clearly not be the cause of “regular” PSP, perhaps the protein that this gene encodes will prove to be part of a molecular pathway critical to the pathogenesis of PSP but not yet investigated carefully.  That could point to scads of new treatment targets for drug developers and maybe even a diagnostic test.  Very cool.

I led a project like this on Parkinson’s disease back in the 1980s and 1990s, though we didn’t have whole-genome sequencing then.  I won’t get into the details, but you can read about the big family I found and worked with here, my subsequent clinical analysis of the family here, the report of the culprit gene here, the discovery of its significance to PD in general here, the development of a diagnostic test based on the gene’s product here, the efforts to prevent PD in lab models by reducing the gene’s product here and an initial safety report on a Phase 1 human trial here.  Maybe that’s why I find Dr. Ringman’s little project so intriguing.

More on the other new grantees in the next post.

All the world wants stages

[This expands on the idea of PSP stages from my last post, so you’ll want to read that one first.]

“Does PSP have stages?” is a question frequently posed by patients justifiably concerned about how far along they are in the degenerative course of the illness and what new symptoms might lie ahead. 

Many people have become familiar, however reluctantly, with the widely used TNM staging system for cancer, where T refers to the size and extent of the primary tumor, N the extent of spread to lymph nodes and M the presence or absence of metastasis to other organs.  Each is assigned a value and summed to generate a stage from I to IV.  For some types of cancer, a letter is appended to denote additional detail.  Complicated but useful. 

Parkinson’s disease takes a simpler approach.  The Hoehn-Yahr Scale, published in 1967, has five stages: 1)  symptoms only on one side of the body, 2) symptoms on both sides or in the face, voice or trunk but no balance problem, 3) balance problem that does not require assistance, 4) balance and/or gait problem requiring assistance, 5) confinement to bed or wheelchair most of the time.  Notice that only the laterality and gait/balance are considered here.  Still, the H-Y Scale is very useful and popular.  The paper by Hoehn and Yahr presenting their scale remains far the most widely-cited publication on Parkinson’s disease.  (A little Internet snark, if you’ll excuse me: My former chairman and mentor, Roger Duvoisin, actually did most of the work on the scale before reporting for duty as a medical officer in the Navy, headed for Vietnam, at which point his two senior colleagues wrote up the paper without him.)

PSP is a complicated disease, with dozens of symptoms that can be very roughly lumped into four main areas: parkinsonism (meaning stiffness, slowness and problems with speech and swallowing), loss of mental function (including both cognitive and behavioral issues), impaired eye movement, and balance problems.  In creating a staging system for PSP, one could follow the cancer model, assigning a rating to each disease feature, summing those, and then defining each stage as a specific range of that total.  Or, one could use the Parkinson’s model, relying on just one feature of the disease that’s easy to evaluate and important to the patient’s daily function.

Now let’s consider the purpose of a staging system.  Its main virtue is convenience.  Ideally, it shouldn’t require any imaging or lab tests and should be usable by any clinician.  If patients and caregivers can apply it, that would be a plus. 

A staging system, like any diagnostic test, should have both validity and reliability, and yes, there’s a difference.  There are multiple subtypes of validity that we need not discuss here.  But in general, validity is the degree to which an accurate answer to the question actually measures what it purports to measure.  For example, if I want to know how severe your PSP is and I only ask about your bladder function, the validity for assessing PSP overall would be low.  But if you know your bladder symptoms well and communicate that information to me accurately, the question would have high reliability.   The opposite sort of example is if I try to assess the severity of PSP by measuring the number of neurofibrillary tangles in the brain.  That would be a highly valid way to assess PSP, but the ability of the available imaging techniques or spinal fluid tests to actually do that is not good enough just yet, meaning that their reliability as a measure of PSP is inadequate.

The staging system that my colleagues and I provisionally devised for PSP and used in our prognostic study described in the August 9 post uses an approach similar to cancer’s TNM system.  It uses only information obtainable from the PSP Rating Scale scores.  It considers only swallowing and gait/balance, as those two issues are the most closely related to long-term complications from malnutrition, aspiration, falls and immobility. 

We assessed the validity of the staging system by showing that stage parallels the same patients’ total PSPRS scores almost exactly.  That’s called criterion validity.  But the proposed staging system still needs to be tested for multiple other kinds of validity as well as for reliability.

Just FYI, here’s how to calculate the stage using our proposed system:  First, rate the following four items from the PSP Rating Scale:

3.  Dysphagia for solids by history

0  Normal; no difficulty with full range of food textures

1  Tough foods must be cut up into small pieces

2  Requires soft solid diet

3  Requires pureed or liquid diet

4  Tube feeding required for some or all feeding

13.  Dysphagia for half a glass of water

0 None

1 Single sips, or fluid pools in mouth or pharynx, but no choking/coughing

2 Occasionally coughs to clear fluid; no frank aspiration

3 Frequently coughs to clear fluid; may aspirate slightly; may expectorate frequently rather than swallow secretions

4 Requires artificial measures (oral suctioning, tracheostomy or feeding gastrostomy) to avoid aspiration

26.  Gait without assistance if possible

0  Normal

1  Slightly wide-based or irregular or slight pulsion on turns

2  Must walk slowly or occasionally use walls or helper to avoid falling, especially on turns

3  Must use assistance all or almost all the time

4  Unable to walk, even with walker; may be able to transfer

28.  Sitting down without using hands

0  Normal

1  Slightly stiff or awkward

2  Easily positions self before chair, but descent into chair is uncontrolled

3  Has difficulty finding chair behind him/her and descent is uncontrolled

4  Unable to test because of severe postural instability

Then total the four scores.  Stage 1 is 1-4 points, Stage 2 is 5-8 points, Stage 3 is 9-12 points, Stage 4 is 13-15 and Stage 5 is the full 16.

Reasonably simple, but it takes training and experience to administer the items accurately and there’s a whole list of little rules and tips that I’ve published in my book but didn’t include here.  I’ll continue to test the validity of the system using a larger dataset and I may fool around with other schemes.  I’ll keep you posted.

Some prognostic help

Sooner or later, most patients with PSP or someone they rely on will ask the doctor, “What’s going to happen next, and when?”  Until now, that question has only been answerable by saying, “Well, the symptoms you have now will slowly get worse and you may develop some additional ones.” or “I don’t know; everyone’s different.”  If the question is, “How long will I survive?” the only available answer has been to quote the published averages for PSP, which have a wide variance. All too often, the answer is, “Don’t worry about that — just take it one day at a time.”

A long-gestating project of mine has finally seen the light of day.  It uses scores on my patients’ PSP Rating Scale (PSPRS) scores gathered from 1995 to 2016 to allow clinicians to predict how much longer it will take for a given patient to reach certain disability milestones and death.  It also proposes a new five-point clinical staging system that we used as some of the disease milestones.  It appears in the August 2020 issue of Movement Disorders Clinical Practice and is available here.

Assisting in the effort was my trusty statistician, Pam Ohman-Strickland, of the Rutgers School of Public Health.  She was also my co-author in the original validation of the PSPRS in 2007.  BTW, if you want to read that paper, here’s your chance. Since then I’ve refined the rules and instructions for administering the PSPRS and that’s available here.

Two undergrads helped out in the new project: Emily Beisser did most of the analysis for the new staging system and Francesca Elghoul helped with data wrangling.

The outcome milestones number 13 in total.  The first seven are severe difficulty with swallowing solids, swallowing liquids, speech, eye movement, general movement, balance and thinking. For each, “severe” is defined as exceeding a specific score on the relevant PSP Rating Scale item(s).  The next five are the stages on the proposed “PSP Staging System” and the last milestone is death.  

We created the five PSP stages by totaling four of the 28 items on the PSPRS: swallowing solids, swallowing liquids, gait, and the ability to return to one’s seat safely from a few steps away without using the hands.  They’re items 3, 13, 26 and 28 on the PSPRS.  The point total for those four items, each rated 0 to 4, are divided into five groups: 0 points, 1-4, 5-8, 9-12, 13-15 and the full 16.  Although this staging rubric uses only two of the many possible deficit areas in PSP, we found that the total of these those four items correlates very closely with the total PSP Rating score.  We chose swallowing and gait/balance as candidates because so many of the serious complications and disabilities of PSP lie in those areas. I’ll devote a future post to the issue of “stages” in PSP.

Tables 3 and 4 in the new paper show the meat of the matter.  You’ll see that the input data are gender, the total PSP Rating Scale score at the time of the visit, and the rate of progression to date.  The last one has to be calculated by dividing the current PSPRS score by the number of months since the onset of the first PSP symptom.

Just a quick caveat: Please don’t try this at home. Many of the exam items on the PSPRS require training and experience to administer correctly; the scale and its instructions are in technical language; and the dating of the onset of PSP symptoms may not be interpreted by the patient or family as an experienced neurologist would.

I hope that these new results, to quote myself from the paper’s introduction, “may influence decisions to retire from work, hire caregivers, alter the home environment, move to a seniors-oriented or institutional living arrangement, decide on a feeding gastrostomy and not least, prepare psychologically for advanced disability and death.”  Until we have a way to prevent or halt the progression of PSP, this will be an important part of how clinicians can help their patients.

PSP clinical trials in the time of Covid

Yesterday’s blog post was my first since the onset of the Covid-19 pandemic.  As you’d imagine, the lockdown has delayed PSP clinical trials.  It’s just too risky to patients, caregivers and staff for an older population to make visits to hospital centers for purposes of research on a chronic condition, even one as serious as PSP. 

The drug companies sponsoring these expensive trials want to wait for a major decline in Covid-19 risk in all of the geographically disparate study site locations. They also want to minimize the risk of another wave a few months later interrupting a study and making them start over.  

The clinical trial closest to launch was from the big Belgian company UCB.  It would test intravenous infusions of a monoclonal antibody directed against the tau protein.  You probably know that two such trials, from Biogen and AbbVie, gave negative results last year, with no efficacy but also no serious or frequent toxicity.  Those antibodies were directed at the “N terminal” of tau, meaning the end of the molecule encoded first during the cell’s manufacturing process.  UCB’s antibody, on the other hand, is directed at the “microtubule binding domain,” which is about two-thirds of the way toward the other end.  So it’s worth testing.  That trial will be delayed to April 2021, per UCB’s present plan.

At least a few months behind UCB’s trial is one from a small Swiss company called Asceneuron (pronounced “uh-SEH-nu-ron”).  I’ve discussed it in a previous post. This oral drug inhibits the detachment of a certain type of sugar molecule from tau, reducing its likelihood of misfolding and aggregating.  I haven’t heard when that trial might be starting and I’m sure that the company is playing it by ear. 

A third trial will test an “anti-sense oligonucleotide,” a strand of RNA injected directly into the spinal fluid in the lumbar spine. It circulates around the brain to reduce the production of tau.  A number of companies have ASO programs for tauopathies. There is also early work on ASO molecules small enough to be dosable by mouth, but those are much further from clinical trials.

A company called Retrotope received FDA permission in April 2020 to start testing an oral drug, RT001, to reduce the level of a toxic process in the brain cells called lipid peroxidation. They are testing this approach not only in PSP, but also in multiple other brain disorders where that defect seems to play a role. No word on a start date.

Another approach is an oral drug from the company called Alzprotect that increases production of a protein called progranulin, a neurotrophic factor (i.e., a normally occurring chemical that encourages the growth or repair of brain cells). The drug is AZP2006 and is in a small trial solely to assess safety in 36 patients in France.

Further from a large-scale trial is a non-steroidal anti-inflammatory drug called tolfenamic acid, which is available by prescription in the UK for migraine. Unlike other NSAIDs, it reduces the production of tau and its abnormal phosphorylation. The drug is in an early-phase clinical trial for PSP at the Cleveland Clinic in Las Vegas.

I’ll keep you updated as required.

Hope matters.

Of spice and dog breeds

Got some catching-up to do.  Since my last blog post about six months ago, I’ve retired from my professorial job at Rutgers, which means I’ve stopped seeing patients.  But I’ll still do clinical PSP trials as a volunteer, so I’ll still see that kind of patient.  Retiring from Rutgers also means that I retire from teaching.  But I’ll continue my work with PSP, so I’ll continue that kind of teaching.  Still working a little on my own research, which is mostly about that cluster of PSP in France.  Then there are all of my non-neurological retirement activities (see spouse for details).  I’ve been neglecting my PSP blog, but that has just changed.

Today a journal article caught my eye.  It found that a slight modification of a naturally-occurring component of turmeric may slow or halt the progression of the tau-based neurodegenerative disorders like PSP and Alzheimer’s disease. At least in cells growing in a dish.

First a little background: You probably know that the brain cells being damaged in PSP contain abnormal clumps of a normal protein called tau.   You also know that the clumps are called neurofibrillary tangles.  In the course of forming the tangles, tau molecules first form smaller accumulations called oligomers (Greek for “a few parts”).  The oligomers are toxic but they’re still soluble in water, like ordinary, monomeric tau (you got it: “one part”).  But the oligomers have an Achilles heel: They tend to form larger clumps, the neurofibrillary tangles, which are no longer soluble in the brain cells’ fluid.  The tangles’ inability to float around and interact with things renders them harmless and means that they serve the useful purpose of taking the toxic, soluble oligomers out of the brain cells’ internal soup.

More background: You’ve heard of turmeric, a popular spice related to ginger.  It’s a traditional remedy for what ails you and some responsible researchers feel that it may actually help certain inflammatory conditions and the metabolic syndrome (high blood pressure, diabetes, abnormal lipids and obesity).  But despite some success in animal models, it has never been proven by modern standards to help any medical condition in actual humans.  Furthermore, we don’t know which of the dozens of chemical components of turmeric explains its apparent benefits.  One minor component of turmeric is curcumin, which by itself is used as a coloring agent in food and cosmetics.  Its chemical structure renders it very difficult to absorb from the digestive tract into the blood or from the blood into the brain.  Here’s the good news: We’ve known for a few years that curcumin, when directly applied to brain cells in a dish, can actually can induce the water-soluble, toxic tau oligomers to form insoluble, harmless neurofibrillary tangles. 

The new journal paper is from neuroscientists at the University of Texas Medical Branch in Galveston and the University of Palermo, Italy.  The group’s leader is Rakez Kayed, PhD of UTMB, a respected and well-published researcher in tauopathies and other forms of neurodegeneration.  The first-named author is Filipa Lo Cascio, PhD, a young post-doctoral trainee in his lab.  They cultured two off-the-shelf types of neural cells and added abnormal tau extracted from autopsied brain tissue from people with PSP, Alzheimer’s disease and dementia with Lewy bodies.  Ordinarily, the abnormal tau would misfold, cause the normal host’s tau to misfold in the same disease-specific way, form oligomers, cause damage, spread to other cells and eventually be taken out of action by forming neurofibrillary tangles.  The curcumin caused the toxic oligomers to more rapidly form tangles, thereby reducing their cell-to-cell spread.  By making the tau less soluble, the curcumin also limited its ability to damage components of the cells with the result of improving the cells’ survival. 

The researchers didn’t actually use curcumin itself, as that compound has no future as a neurological treatment because, as mentioned, it can’t get into the brain. So they tweaked its structure by replacing some hydroxy (-OH) and methoxy (-O-CH3) groups (don’t worry about it) with fluorine atoms.  The resulting compound, which they dubbed CL3, had the same beneficial effect regardless of whether the abnormal tau introduced into the cells was from people with PSP, Alzheimer’s or dementia with Lewy bodies. 

The next step is for another lab to replicate the results using different methods.  At the same time, researchers could try the experiment in mice that have received an abnormal tau gene that forms aggregates and kills their brain cells.  That’s currently the best lab model for PSP and the other tauopathies.  But the multiple examples of drugs that prevented this sort of mouse tauopathy and then failed to prevent PSP in clinical trials show that the mouse models, albeit based on human tau, are inadequate as surrogates for people with real PSP or other tauopathies.

The experiments of Lo Cascio, Kayed and colleagues also confirmed that the aggregates forming from tau taken from people with different tau disorders differ from one another in some other important ways.  That’s the new, hot idea of tau strains – they’re like dog breeds.  They’re all tau, but they differ in some important details and when they reproduce (i.e., by templating their abnormal folding pattern onto normal copies of tau in a host cell), their specific variation continues in the next generation.  More about tau strains soon.

Now let’s see if I can keep this up.

The elusive limelight

No rare disease advocate wishes illness on anyone, but we do all hope that one of PSP’s inevitable sufferers will happen to be a celebrity. 

When Michael J. Fox announced his diagnosis, awareness of Parkinson’s disease and fundraising for its research took off.  Amyotrophic lateral sclerosis, its prevalence no more common than that of PSP, would still languish in obscurity without Lou Gehrig.  Awareness that Alzheimer’s disease was not “accelerated aging” nor a circulatory problem was boosted early on by the plights of Rita Hayworth and more recently of Ronald Reagan, Glenn Campbell and Pat Summitt.  Robin Williams brought Lewy body dementia to popular consciousness for the first time.

PSP has never had a celebrity advocate who was an affected person.  The only real candidate emerged in 1999, when British comic actor Dudley Moore announced his diagnosis.  Shortly thereafter, a profile of Mr. Moore on the TV newsmagazine “20/20” brought the disorder some degree of attention.  In fact, at least a couple of new patients came to me after recognizing their own neurological deficits in the 20/20 piece.  A few months later, Mr. Moore himself became my patient.  He told me that he appreciated that PSP needed a celebrity spokesperson and offered to help in fundraising, but declined to become its “poster boy” (his words, not mine).  He did participate in one fundraiser before his death in 2002 and I never tried to wheedle any video clips, interviews or other forms of publicity out of him.

CurePSP did attract as its spokesperson for a number of years a celebrity whose father had PSP.  Starting in about 2005, Patricia Richardson, an accomplished actor who in the 1990s had played opposite Tim Allen in the TV sitcom “Home Improvement,” joined CurePSP’s Board of Directors.  When we appeared at events together, she was admirably persistent in prodding me to translate my scientific presentation into language appropriate to the audience.  She was generous with her time for CurePSP’s outreach and support services.  But in 2015, she and CurePSP parted ways. 

About a year ago, Linda Ronstadt announced that she had been diagnosed with PSP.  The CurePSP leadership immediately attempted to propose a spokesperson relationship, but were unable to establish contact at all.  In a September 2019 “New Yorker” magazine profile ahead of the release of the new documentary, “The Sound of My Voice”, she said, “I’ve just accepted it. There’s absolutely nothing I can do. I have a form of Parkinsonism that doesn’t respond to standard Parkinson’s meds, so there’s no treatment for what I have. It’s called P.S.P.—Progressive Supranuclear Palsy.”  But the documentary itself mentions only “Parkinson’s disease.”  (A digression: Perhaps, like many patients and caregivers, Ms. Ronstadt is under the misimpression that PSP is only a more severe form of PD, in which case she may think that someone with PSP could be said have both, one being a subset of the other.  I won’t share my own diagnostic impression on PD vs PSP based on her current speech, facial movement and eye movement as they appear in the documentary.  I’ve been around long enough to know that diagnoses relying of such fragmentary data are risky.) 

So PSP still struggles to enter public consciousness. A glimmer of hope appeared on major network TV on January 7, with the premiere of the NBC series, “Zoey’s Extraordinary Playlist.”  The star hallucinates that others communicate their feelings in the form of impromptu song-and-dance numbers.  Her father, with advanced PSP, is played with admirable accuracy by Peter Gallagher.  Sure enough, in one of the pilot episode’s musical scenes, the father, aware of his daughter’s multiple professional and personal anxieties, breaks out of his immobile, mute state into a tender song of encouragement.  The script does not include the term “PSP” or “progressive supranuclear palsy” but press blurbs and cast interviews do so.  Of course, this does not provide a real-life celebrity spokesperson, but at least it’s publicity.

Of course, I hope that no celebrity – or anyone else – ever comes down with PSP.  But once the inevitable happens, perhaps he, she or a loved one will be willing to sacrifice some time, energy and privacy to the cause. 

Your own one- or two-year crystal ball

You may know that for many years one of my jobs at CurePSP is to chair the grant review. Twice a year we have a deadline for researchers in either academia or the private sector to apply for up to $100,000 for work related to PSP or CBD. It’s very competitive, as we receive about 20-25 applications a year from some top research groups and fund only about 5-7 of them. We welcome purely clinical projects as well as laboratory work. The term of the grants is 1 or 2 years. Here are the 4 successful awardees from our Fall 2019 grant cycle:

Lukasz Joachimiak, The University of Texas Southwestern Medical Center, Dallas: Structural basis for tau strain conformation in CBD and PSP

In the brain, the tau protein can form an altered shape that clumps together in an aggregated form.  This study will isolate the tau protein from healthy, PSP, and CBD patient brain tissues. Specialized research tools will be applied to determine how the abnormally folded shape of tau differs from the tau from healthy brains. Understanding the fine details of how the tau protein changes from a normal shape to the different “bad” forms found in disease will provide the blueprint for designing new methods to detect and prevent these devastating diseases in patients.

David Butler, Neural Stem Cell Institute, Rensselaer, NY: Bifunctional intrabodies to lower tau

The goal of this project is to develop therapeutic agents that will prevent tau accumulation and associated death of brain cells with novel antibody-based reagents (termed intrabodies). Intrabodies are antibodies expressed within brain cells, while antibodies produced by the immune system or administered by vein do not penetrate brain cells.   These antibodies are highly selective for tau, and they have been engineered to target tau for degradation using the cell’s normal clearing process. The study’s central hypothesis is that targeted degradation of tau protein will reduce the amount of tau available to misfold and thus reduce cell death.

J. Mark Cooper, University Hospital, London, UK: The influence of TRIM11 on tau, aggregation, release, and propagation

In 2018 this research group identified the TRIM11 gene as a risk factor for PSP. This study will investigate the effects of a the protein encoded by that gene on toxic tau protein aggregation in the brain. It is believed to play a role in regulating the levels of some proteins within the cell, in particular proteins that may form aggregates. The study will use models of brain cells grown in the laboratory to focus on how changes to TRIM11 influence tau protein regulation, in particular its tendency to aggregate. These findings may help to identify potential therapeutic targets to modify PSP disease progression.

K. Matthew Scaglione, Duke University, Durham, NC: Small-molecule regulation of a protein quality-control E3 to treat PSP

The protein Hsc70 or “CHIP” accelerates the removal of tau from the brain. This project intends to identify compounds that stimulate CHIP functions.  One important such function is as an “E3” enzyme, which is an important part of one of the brain cells’ “garbage disposal” mechanisms called the ubiquitin-proteasome system (UPS).  E3 allows the UPS to recognize specific proteins for appropriate disposal.  Finding new compounds to stimulate this function is an important first step toward developing small (that is, orally dosable) molecules to slow or prevent the progression of PSP and CBD.

(If those descriptions sound like they’re not my own writing style, it because each was provided by the researchers themselves and then edited by me to fit what I think, based on little evidence, to be the technical background of this blog’s readers.)

I’ll update you on the progress of those projects once they’re publicly presented or published over the next 2 or 3 years.

A sidebar about PubMed: If you didn’t already know, you can see these, or any, researchers’ previously published work by typing a name into the search line at PubMed. Enter the last name, then the initials. To narrow it down, add a topic (like tau or neurodegenerative disease). The initial display lists papers satisfying the search terms in reverse chronological order. Clicking on one of them brings up the authors, institutions and a half-page, technical-language summary. There’s always a stack of links to related papers, including subsequent ones that cite it. Clicking an author’s name will produce a list of his/her other publications. Plus, for some articles, the whole text is available via a clickable link, sometimes for free, usually for an exorbitant fee. Have fun!

He said he was just going out to buy cigarettes . . .

Yeah, yeah.  I know I haven’t posted anything in the past two years other than responses to questions.  No, I don’t know why.  But those who stray can be redeemed, I’m told.  So here’s the first installment of a quick and dirty summary of most of the important news in the world of PSP from 2018 and 2019:

I’ve mentioned with breathless hope the two large trials of monoclonal antibodies directed against the tau protein, one sponsored by Biogen, the other by AbbVie.  Both were designed to detect slowing of the progressive decline in function as measured by the PSP Rating Scale.  Bad news.  Back in July 2019, AbbVie ended its study prematurely after an interim analysis showed no benefit and that continuing the study would be futile.  Biogen completed its study in October and announced in early December that its results were no better than AbbVie’s.  In each case, there were no important adverse effects.  But each company is continuing development of its respective antibody for Alzheimer’s disease.  Those results won’t be available for a few years.

But there’s still hope for anti-tau antibodies in PSP.  Both the Biogen and the AbbVie antibodies were designed to recognize the “N terminal,” so-called because of its unattached amino group, which is based on nitrogen.  (The other end is called the “C terminal” because of its unattached acid group, which is based on carbon.)  But other drug companies are developing antibodies targeting other parts of the tau molecule, and they haven’t announced any intention to abandon those programs.  Next out of the gate will be the big Belgian company UCB, whose antibody targets the “microtubule-binding domain” of the tau molecule, which is much closer to the C terminal.  Its Phase 1 trial has started at selected centers in Europe and in the works is a larger, Phase 3 trial that will include sites in the US.  Still other anti-tau antibodies are being tested in Alzheimer’s by Lilly, Roche/Genentech and Johnson & Johnson, and there’s no reason to think that those antibodies couldn’t work just as well against PSP.

Other treatment ideas are approaching clinical trials as well.  The closest are the “OGA inhibitors,” which I described in a 2017 post.  Three companies are working on those: Asceneuron, Merck, and Lilly, though the last is just targeting Alzheimer’s so far.  I hope that Asceneuron’s trials will start in 2020, though my PSP treatment hopes have been dashed before. Also on deck are the “anti-sense oligonucleotides,” or ASOs, which prevent the tau molecule from being manufactured in the first place.  Such drugs are already on the market for Duchenne muscular dystrophy, spinal muscular atrophy and hereditary transthyretin amyloidosis, each of which affects the muscles or nerves rather than the brain and are not tau disorders.

You’ll recall that a new set of diagnostic criteria for PSP was published in 2017.  It’s called the MDS-PSP Criteria after the Movement Disorder Society (now renamed the “International Parkinson and Movement Disorder Society” for obscure reasons), which sponsored the project.  New criteria were necessary to recognize early stages of PSP, when enrollment in treatment trials (and later, in treatment) would be most advantageous, and also to recognize the recently-described PSP subtypes.  In the past two years, a few studies have validated the criteria to some extent by comparing autopsy results with how closely patients satisfied the criteria during life.  Just last month, researchers in the UK found that applying the new criteria allowed them to expand their population with PSP by 74%.  The new patients were those with the “atypical” forms of PSP that went unacknowledged by the older criteria published in 1996.  The thing is, most of the “atypical” PSP patients will evolve to also satisfy the criteria for typical PSP, which we call PSP-Richardson syndrome, or PSP-RS.  So they would eventually have been recognized as PSP, but usually after years of erroneous diagnoses, unnecessary tests and futile, expensive and inconvenient treatments.

Quite enough for now.  I’ll continue these updates more faithfully, only next time it will get more technical.  Careful what you wish for.

This orphan has many parents

The Orphan Drug Act of 1983 was a game-changer for rare diseases.  A result of lobbying by patient-led groups such as NORD with bipartisan political support, its principal author was the liberal Democratic Congressman Henry Waxman and its signer was President Reagan.  The rate of FDA approval of drugs for orphan diseases increased from fewer than one per year before 1983 to an average of 13 per year over the ensuing decades.  The ODA provided drug companies 7 years of new patent protection, financial subsidies in the form of grants, a fast-track approval process and last but not least, a tax credit for 50% of the development costs.

A disorder qualifies for “orphan” designation under the ODA if its point prevalence in the US is fewer than 200,000.  PSP easily meets that criterion, with about 5,000 diagnosed cases or 20,000 if you count those who undiagnosed but potentially diagnosable.

PSP’s transition from an orphan to an object of loving care has been remarkable.  There are several reasons:

First, a drug that works for PSP may also work for other tauopathies, including Alzheimer’s disease.  Of course, a huge potential market exists in the ascendancy of AD as a major epidemiologic challenge for the Boomer Generation and beyond.

Second, the disappointing results of clinical trials of drugs addressing the beta-amyloid aggregation of AD turned the research world’s attention to tau aggregation as the key to AD prevention.

Third, PSP, as a “pure tauopathy” offers a good, clean “test bed” for anti-tau agents.  (We now know it’s not so pure, but close enough for present purposes.)

Fourth, neuroprotective trials are easier in PSP than in AD despite the recruitment difficulty arising from the disease’s rarity.  One reason is that PSP, unfortunately, progresses more quickly than AD.  (Aside: A “neuroprotective” trial attempts to reduce the rate of worsening of the disease, usually without improving the existing symptoms.  A “symptomatic” trial attempts to improve existing symptoms without regard to the long-term progression or outcome.)  Demonstrating that a drug slows a disease’s progression requires fewer patients and a shorter treatment period when the untreated disease progresses more rapidly.  This translates into cheaper development costs and less development time.

Fifth, in the absence of a proven biomarker for AD, clinical trials must rely on neurological exams and reports of daily activities by patients and caregivers.  No such clinical scale accomplishes this adequately for AD, but the PSP Rating Scale does so for PSP.  (Bragging point disguised as a disclaimer: I developed the PSPRS.)

But the House of Representatives’ version of the new tax reform bill eliminated the tax credit in the Orphan Drug Act.  The thinking was that drug companies often charge prices for those drugs far in excess of their development costs, thereby defeating the original intent of the ODA to support development of drugs without a reasonable expectation of profitability.  The drug companies can usually get away with those prices because the patients are desperate and because the insurance companies providing prescription coverage want to avoid lawsuits and public-relations disasters.  Besides, the insurors can just raise their premiums to spread the cost over their other subscribers.

The other concern in the House was that drugs developed under ODA protection may then find use against more common conditions with highly profitable results.  Some examples are Cialis (developed for pulmonary hypertension, then for erectile dysfunction), Botox (dystonia, then wrinkles) and Provigil (narcolepsy, then off-label as a cognitive enhancer) .  A PSP drug subsequently used for AD could become another example, as pointed out above.

The final tax reform law is a compromise.  It reduces the fraction of the development costs that can be taken as a tax credit from 50% to 25%, not to zero.  How will this affect the drug companies’ calculations regarding future orphan drug development?  I haven’t a clue.  But my attitude toward this complicated situation is that patients with PSP should be glad that their disease is of interest to drug companies, even if that’s only a by-product of their interest in AD or some other way to game the ODA.

Some think tank now needs to figure out just how much credit the ODA deserves for recent decades’ abundance of new drugs for orphan diseases.  Maybe it’s not an economic issue at all.  Maybe it’s just that recent basic scientific breakthroughs have created more drug targets.  Or maybe the drug companies have figured out that they can charge tens or hundreds of thousands of dollars per year for a drug and get away with it.  Either way, maybe the ODA is unnecessary or needs to be radically revised.  One can hope that if the current work on PSP results in a mega-expensive AD drug that strains our present health care model, maybe the result will be a truly universal health care system in the US.