Monthly Archives: January 2020

The elusive limelight

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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

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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 . . .

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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.