For as long as I’ve directed the research grants program at CurePSP, I’ve been a champion of the investigator-initiated approach. Let the experts decide what’s scientifically ripe and feasible for them, I say. I’ve seen too many RFAs produce opportunistic applications that are a stretch for an investigator both intellectually and practically.

But I thought it was best to compromise that principle by creating this “Road Map to a Cure.” It presents a general approach to developing neuroprotective treatment for PSP that builds on recent advances and hot ideas, interacts with the private sector, and is feasible with present technology. Perhaps best of all, its definitions are flexible enough to accommodate a wide variety of investigator-initiated ideas.

In developing the Road Map, I collaborated with Yvette Bordelon, a movement disorders specialist at UCLA and Chair of the Research Committee of CurePSP’s Board of Directors; and Jeff Friedman, a pediatrician/biochemist at Friedman Bioventures and Scripps and a member of CurePSP’s Board.

Road Map to a Cure

As you can see, the Road Map chooses three general hypotheses: a genetic etiologic component, a prion-like (the preferred term is “templating”) mechanism, and a problem with protein folding and management. It also identifies two broad categories of experimental tools that need improvement: animal (or cellular) models and human biomarkers. The Road Map then seeks to develop treatments based on one or more of the three hypotheses and using one or both of the two tools. Then comes the familiar the cascade of treatment development, from target identification to in-vitro or cellular screens to more complex model organisms to early-phase humans trials to late-phase trials.

Of course, some treatments may be ready for testing in animals or humans right now without the preliminary steps, and that would be great.  Will CurePSP triage out any applications lying outside of this development model? Not at all. The Road Map is formulated more as a general guide and we recognize that there are other paths.

We also recognize that the Road Map ignores important things like symptomatic or surgical treatments, studies of exogenous risk factors, descriptive and nosologic studies and, perhaps most important, completely new and risky ideas.

The Road Map, as you’ve guessed, is designed partly as a fundraising tool that allows potential donors to understand how scientists would spend their money. The donors deserve to know that and are quite capable of understanding it if we scientists just take the trouble to explain it to them.

Silly me. I thought I could write some posts in technical language and others on different topics in plain English. But I find that I just don’t have the heart to leave my non-technical readers in the dark about exciting research findings, even if the payoff for patients is years away. So here’s a brief, non-technical translation of my last post on DNA methylation.

A paper in a prestigious journal this week reports that the DNA of people with PSP has an unusual pattern of small chemical markings in a few areas, including the area that includes the gene that makes tau protein.

Time out for some basics:

DNA is the chemical that bears the genetic code. It’s like a language with an alphabet of only four letters. Each word has three letters and there are 20 available words. The “letters” are A, C, G and T, which are abbreviations for the four chemical components that make up the DNA strand. Each three-letter “word” specifies an amino acid. A string of amino acids that the cell produces according that that instruction (like a sentence, to continue our analogy) is called a protein. All of the chemical processes and structures of the body rely on proteins of many different varieties that are determined mostly by the order of their amino acids.

Tau is the protein that forms the abnormal blobs in brain cells in PSP, called “neurofibrillary tangles.” Its normal function is to help maintain the internal skeleton of the brain cells, which doubles as monorail system to transport nutrients to where they’re needed.

These chemical markings, called “methyl groups,” are very simple – each is just one carbon atom with three hydrogen atoms on it. It’s been known for many years that such “methylation” of the amino acids in DNA is one way to regulate the coding of the DNA into proteins. In PSP, the tau protein is abnormal in several ways, and abnormal methylation of the tau protein’s gene, it’s now been discovered, could be the reason.

We already know that the gene that encodes the tau protein is abnormal in other ways. But those are actual genetic mutations – alterations in the DNA code itself. The new research article concludes that the mutation in the order of bases in the DNA causes the abnormal methylation, which then causes the damage of PSP.

We’ve also long known that methylation can be influenced by the chemical environment of the cell, examples being certain toxins or nutritional deficiencies. So this new finding suggests that we should look more closely at those sorts of things as possible causes of PSP. It also suggests that drugs that affect methylation could potentially stop or slow progression of the disease.

As you’d imagine, this opens the door to a whole new area of research in PSP. These are exciting times!

If you’ve read the technical-language post below and are intrigued but confused, here’s a plain English version.  Use the Comments section below to tell me if it’s clear enough for an educated non-technical reader.

The current issue of the journal Movement Disorders includes two articles on a recent trial of an experimental drug for PSP.  The journal’s editors asked me to write an “editorial” (actually, an overview for the sake of perspective) for the journal’s technical readers.  That appears in the same issue and its main point is this:

The two original papers in Movement Disorders report a trial of the experimental drug “tideglusib” in 146 people with PSP.  (The drug is not approved in any country or available in pharmacies.)  The study took place in 2011 and 2012 at multiple institutions in the US, Spain, Great Britain and Germany.  Like any good trial, it included administration of a dummy treatment (a “placebo”) to some of the people with PSP randomly chosen as a comparison group.  The neurologists doing the study tested all of the subjects with the PSP Rating Scale, which is the standard test used in research on PSP, at the start and end of the one year of treatment.  No one expected tideglusib to give improvement over time; the best outcome hoped for was that the rate of decline would be slower on tideglusib than on placebo.

As a kind of supplementary part of the study, 37 of the 146 patients also received a brain MRI at the start and end of the year of treatment in addition to the PSP Rating Scale.  The idea was to compare the patients on tideglusib with those on placebo with regard to the amount of shrinkage (“atrophy”) of various parts of the brain over the year of the study.  This was added mostly as a test of the ability of MRI to provide an objective test to supplement the PSP Rating Scale, which uses interview questions and physical examination.

The overall study, unfortunately, showed absolutely no benefit of tideglusib over placebo on the PSP Rating Scale.  But the sub-study using MRI did show quite a difference, 58% less atrophy of the cerebrum on tideglusib relative to placebo. 

Now, some researchers have known about this result for several months because they heard its principal author, Dr. Günter Höglinger of Munich, Germany, present it at conferences.  Most experts whom I have spoken to find it hard to accept that the MRI could show an effect of the drug without any effect on the PSP Rating Scale or on any of the other physical or psychological examination measures that were applied.

Some of the skeptics point out that the group of 37 receiving the MRI may have been too small to be representative of the overall group of 146 and that the 9 patients on placebo may have been different from the 28 patients on tideglusib even before the study began.  It’s true that these numbers of patients are awfully small for drawing definitive conclusions and raise the possibility of a statistical fluke.

Others object on grounds that the most pronounced effect on the MRI was in the areas of the brain least affected in PSP.  But since I’m a “glass-half-full” kind of guy, I see this as a clue to guide further research.  Maybe brain tissue in the more advanced stages of PSP is beyond help of this particular drug, and only the more PSP-resistant, slowly-degenerating parts of the brain responded.  If so, maybe that means that we should look for ways to improve tideglusib rather than discarding it because it gave no outwardly measurable improvement.  Another conclusion is that we should work on ways to diagnose PSP earlier, when no part of the brain has progressed beyond the ability of a drug like tideglusib to help.

In another post, I’ll explain what tideglusib does in brain cells.  It’s complicated.

My inaugural post!  Here goes.

The current issue of Movement Disorders has two papers on a late Phase II study of the GST-3β inhibitor tideglusib in PSP.  The first, by Eduardo Tolosa et al, reports the failure of the drug to slow progression as measured by the PSP Rating Scale and a number of other clinical scales.  But the second, by Günter Höglinger et al, analyzes a subgroup of patients from the same study who had MRIs before and after treatment.  They found 58% less progression of cerebral atrophy in the active drug group relative to placebo.  Most of the effect occurred in the parietal and occipital lobes, the neocortical areas least affected in PSP.

Full (really full) disclosure: I was a one of the co-I’s in the study, though not one of the sites doing the MRIs (they were the European sites); the primary outcome measure was a scale that I devised and published; I consulted for the industry sponsor in the study design; Günter Höglinger is my very good friend (as is Eduardo, but his paper isn’t the controversial one); and I have an editorial in the same issue of Movement Disorders trying to interpret the findings.  Is my bias reduced by my inability to figure out in which direction it points?

Anyhow, I’ve heard various reasons why this couldn’t possibly be a real neuroprotective effect, and none of them are all that convincing.  But I don’t want to bias you.  Discuss.