Today reader RW posted a comment asking about the status of the NIO752 trial. I thought my answer was so, SO well-crafted and informative that I just had to promote it from a comment response to a full blog post, and here it is:
RW:
First, for the benefit of your fellow readers, NIO752 is the anti-sense oligonucleotide from Novartis. An ASO is a short span of RNA injected into the spinal fluid space. In this case, the injections are given four times: every three months for a year. The drug reduces production of tau at its source — where its gene is transcribed into protein. In my opinion, it’s more likely to work against PSP than any other past or current experimental drug. However, the need for the spinal injections could limit its appeal, especially if one or more of the oral (i.e., more convenient) drugs currently in more advanced stages of clinical testing reach the market first. The Phase 1 NIO752 trial ended a month or so ago and Novartis, apparently, is still crunching the numbers. It’s typical for that to take 2 or 3 months, so I wouldn’t infer anything from it. Keep in mind that this was only a Phase 1 trial, powered to assess safety, not efficacy. I haven’t heard anything through the grapevine about major safety problems during the trial, but you never know what the actual data might show or how the company might react in terms of continuing to advance the drug into a Phase 2 trial. LG
I want to tell you about one small study that, although it needs expansion and confirmation, is exciting because it could allow a future PSP neuroprotective treatment to be prescribed before having to wait for symptoms to appear.
You’ve probably heard of the protein “alpha-synuclein” (pronounced “suh-NOO-klee-in”). It has a long list of normal functions in our brain cells, but in its various misfolded forms, is the major component of abnormal protein aggregates of Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. Now, a blood test for alpha-synuclein might actually provide a way to diagnose PSP despite the fact that tau, not alpha-synuclein, is PSP’s abnormally aggregating protein.
The new paper in the journal Biomedicines by researchers at the University of Catanzaro in Italy, have found the concentration of alpha-synuclein to be slightly greater in the red blood cells of people with PSP than in healthy people or those with PD. The graph below from the journal article (with my explanatory notes and arrows) compares results from the eight people with PSP to 19 with PD and 18 healthy control participants. The vertical axis is alpha-synuclein concentration expressed in nanograms of alpha-synuclein per milligram of red blood cells.
One paragraph of technical background on alpha-synuclein: While alpha-synuclein does most of its work in brain cells, helping in neurotransmitter release and protect against mis-application of the cell’s “suicide” program (called “apoptosis”), it’s also abundant in red blood cells. In fact, it’s the second-most-abundant protein in red cells after, of course, hemoglobin. The job of alpha-synuclein there is to help to stabilize their red cells’ outer membranes and to help in the process of removing the nucleus from the red cells’ precursor cells in the bone marrow. Nucleus removal makes more room for hemoglobin and more important, allows the cells to deform more easily as they pass through capillaries. That deformation provides a signal to the hemoglobin to release their oxygen to the tissue.
Back to business: The graph shows clear overlaps between PSP and the other groups, but the medians do differ to a statistically significant degree. The short arrow by the vertical axis points to a value of 85.06 ng/mg, which the researchers chose in retrospect as the best cutoff between normal and abnormal. Using that definition, the sensitivity of the measure was 100%, meaning that all eight participants with PSP had an abnormal result (that is, a value higher than 85.06). The same cutoff yielded a specificity of 70.6%, which is the fraction of the PD and HC participants with a normal result; in other words, the fraction that would be diagnosed correctly as “non-PSP.”
But if only 70.6% of the participants with “non-PSP” have a normal test result, that means that the other 29.4% have an “abnormal” result and would be falsely diagnosed with PSP. PD is about 20 times as common in neurological practice populations as PSP, so for every 1,000 patients who might have PSP or PD and see a neurologist, about 50 have PSP and 950 have PD. If you do the red cell test in all 1,000, that means that 29.4% of 950, or 279, will have an abnormal result. If all 50 with PSP also have an abnormal result, that totals 339 people with abnormal results, of whom 279 (a whopping 82%) don’t actually have PSP.
So, a neurologist seeing a result below that 85.06 cutoff would be able to reassure patient that they do not have PSP, with, of course, the usual precaution that outliers and lab errors do exist. A result above the 85.06 cutoff would prompt other diagnostic tests with greater specificity, although probably with greater expense, inconvenience and/or discomfort. I hasten to add that like any new research finding, this needs confirmation by other researchers using other, larger patient populations in all stages of illness.
You may recognize this result as the definition of a “screening test.” That’s a relatively inexpensive, convenient, safe and sensitive test suitable for use in large populations of asymptomatic or at-risk people. If a screening test is positive, further testing, or at least close observation, is advised. A good example is a routine mammogram, where a negative reading is great news and a positive reading prompts further testing. In this example, that testing usually results in a diagnosis of a benign cyst or scar or something else other than breast cancer, and the few women whose mammogram abnormalities turn out to be breast cancer and whose lives are saved by the ensuing treatment will be very glad to have had that screening test. A similar situation could develop for PSP once we have an effective way to slow or halt progression of the disease. That’s what the PSP neuroprotection trials currently under way hope to accomplish.
It seems unlikely from the new data that red cell alpha-synuclein concentration would ever offer enough specificity to diagnose PSP to the exclusion of non-PSP. But people with a positive test could then have, perhaps, an MRI, where certain arcane measures of the midbrain and basal ganglia could provide diagnostic information with the specificity for PSP that’s missing from the red cell alpha-synuclein test. In this way, the red cell alpha-synuclein is similar to neurofilament light, a protein elevated in the blood and spinal fluid in PSP but also in several other neurodegenerative diseases.
The senior author of the new paper is Dr. Andrea Quattrone, whom I know well and can vouch for. He is an internationally recognized leader in discovering diagnostic markers for PSP. The first-named author is Dr. Costanza Maria Cristiani.
More technical stuff in italics: Why should alpha-synuclein occur in elevated amounts in a tau-based disorder like PSP? Cristiani et al hypothesize that the red cells absorb most of their alpha-synuclein from the plasma (the liquid component of the blood) rather than being “born” with it in the bone marrow. They cite previous findings that excessive tau protein impairs the blood brain barrier, which could allow alpha-synuclein, an abundant protein in the brain, to leak into the blood, where it’s “scavenged” by the red cells. An obvious next step is to check other tauopathies such as Alzheimer’s disease for elevated red cell alpha-synuclein.
And now, on a personal note: My career as a researcher started in Parkinson’s disease and for a decade starting in 1986, I led the clinical component of the project that discovered that alpha-synuclein was related to PD. It began when I found and painstakingly worked up a large family with a rare, strongly inherited form of PD . That work, which included many collaborators I recruited in multiple institutions and countries, showed that family’s illness to be caused by a mutation in the gene encoding alpha-synuclein, which had not previously been suspected of any relationship to PD. Soon thereafter, others found alpha-synuclein as the major constituent of Lewy bodies (the protein aggregates of PD) in individuals with ordinary, non-familial PD without the mutation. Now, alpha-synuclein treatments and diagnostic tests are being developed for PD. So, if a critical diagnostic test for PSP, the disease to which I’ve devoted most of the more recent decades, should turn out to be based on alpha-synuclein, that would nicely satisfy the scientific narcissist in me.
In July 2023, I posted a guardedly optimistic report on the launch of a small, Phase 2a trial in South Korea of the drug GV-1001, with the generic name “tertomotide.” Three weeks ago (sorry for my delayed vigilance on your behalf), the company released some of the results. The headline was that the drug failed to show benefit in slowing the rate of progression on the PSP Rating Scale. Nevertheless, the company, GemVax, said they remained optimistic and would proceed with plans for a Phase 3 trial in North America and elsewhere.
Here’s the deal in a bit more detail. I say “a bit” because it’s not as much detail as I’d want to see. The trial was only 6 months long and the plan was for only 25 patients in each of the three groups: higher dose, lower dose and placebo. That’s too brief and too small to demonstrate a realistic degree of slowing of progression. The best longitudinal analysis of PSP to date calculated that to demonstrate a 30% slowing in a 12-month trial would require 86 patients per group. Shorter trials and more modest slowing would require even more patients than that. But early-phase trials like this are mostly about safety, not efficacy.
The results for the low-dose and placebo groups appears below, just for the PSP-Richardson patients:
The vertical axis is the average improvement (downward) or worsening (upward) in the total PSP Rating Scale relative to the patient’s own baseline score. (On the PSPRS, 0 is the best and 100 the worst possible score, and the average patient accepted into a drug trial has a score in the mid-30s.) At 3 months, neither group showed much change. But at 6 months, the placebo group had deteriorated by 4 points but the active drug group had remained close to its baseline. So, that looks like a benefit, but the wide standard deviation (the vertical “whiskers” at 3 and 6 months) were too large to support statistical significance (i.e., to rule out the possibility of a fluke result). Hence the negative headline, but you can see why the drug company felt encouraged by the result.
A more complicated but statistically more valid way to look at the same results appears below. This graph applies to both PSP-Richardson and PSP-Parkinson patients, hence the larger Ns:
This time the vertical axis is “least square mean change from baseline.” That uses a statistical technique called “mixed-model repeated measures” to compensate for statistical noise in the results. The basic shapes of the active drug and placebo curves look similar to the raw score graph. But now, the two lines have the same slope between 3 and 6 months, suggesting that their rates of progression over that period were the same. The interval from baseline to 3 months did have different slopes, favoring active drug. So, this could mean one of 3 things:
There’s a neuroprotective effect (i.e., a slowing of the progression rate) that lasts only 3 months, at which point the two groups proceed to progress at the same rate;
There’s a symptomatic improvement by the 3-month point that persists to the 6-month point, but no protective effect at any point; or
The trial’s small size, wide standard deviations, paucity of evaluations and short duration make it impossible to draw any conclusions about symptomatic or neuroprotective efficacy.
I’ll vote for Option 3.
The data for the high-dose group, which received twice the lower dose, is not presented in the company’s press release. However, the high-dose group was included in the poster at the Neuro2024 conference (CurePSP’s annual international scientific meeting) in Toronto in October. It did not show the possible benefit that the low-dose group showed. So, that’s a little discouraging, but it’s not unheard-of in pharmacology for a higher dosage regimen to do something extra via a different chemical mechanism that counteracts some of the benefit of a lower dosage. So, that doesn’t worry me much.
Now, the issue is just how safe and tolerable the drug was. The press release only says, “The safety profile of GV1001 in the Phase 2a PSP Clinical Trial was consistent with prior safety data. GV1001 was generally well-tolerated with no serious adverse events related to the drug reported.” I’ve seen the actual numbers, and the press release is right. All of the adverse events, and there were very few, were things common in this age group or complications of PSP itself.
So, that’s probably more information than you wanted about GV-1001, or maybe it’s a lot less than you’d have liked. (I’m in the latter category.) Bottom line is that the results were good enough to justify a Phase 3 trial, which is slated to start in 2025, and that’s really good news.
Note: The text in italics explaining the two graphs and detailing the drug side effects are corrections or additions to my originally posted version. I thank Roger Moon, Chief Scientific Officer of GemVax, for supplying this information after he saw the original post.These changes do not alter my conclusions.
On November 3 of this year I posted on some work with a zebrafish model of tauopathy showing that a class of drug called carbonic anhydrase inhibitors could slow disease progression. Those drugs are commonly prescribed for glaucoma and other conditions. One insightful commenter has asked if it might be possible to use an existing patient database to search for a correlation between CAIs and PSP risk.
There has been one such attempt, but it included too few patients to answer this question. Earlier this year, Jay Iyer and colleagues (including me) at multiple institutions used a database of 305 patients with PSP observed over a 12-month period to look for any relationship between concomitant drug use and rate of progression on the PSP Rating Scale. It found that benzodiazepines were associated with more rapid progression. Here’s the paper. The table’s “F value,” as the caption indicates, measures the “interaction between change in PSPRS scores and time.” That’s a sophisticated version of the rate of progression.
But CAIs are too rarely prescribed to show up in that type of analysis. In fact, the statistics considered only those drugs used by at least 10% of the patients, as lower frequencies would not have produced statistically significant results.
This approach, seeking a relationship between the risk factor (medication use) and an outcome (disease severity) is only one way to approach this problem. Another is to compare people with PSP to people without it with regard to the risk factor. Another is to compare people with the risk factor to people without it with regard to the frequency of the disease. For a disease as rare as PSP and a risk factor as rare as CAIs, one would need a huge database, like those maintained by national health care systems. Unfortunately, no such analysis of PSP and CAI use has been attempted to date, but in theory, it can be done despite PSP’s misdiagnosis rate in the general population outside of dedicated movement disorder centers.
I want to draw your attention to a new PSP-related blog, started by CurePSP on October 22. In keeping with CurePSP’s overall mission, the blog concerns not only PSP, but also corticobasal syndrome (CBS) and multiple system atrophy (MSA), which can be difficult to distinguish from PSP, especially in early stages.
The one post so far is an excellent discussion of speech-assistive devices and voice banking by CurePSP staffers Courtney Malberg and Oscar Sullivan. Although I’m CurePSP’s Chief Clinical Officer, I’ve provided no advice nor content for the blog to date and haven’t been asked to. That’s the way it should be — I’ve got my own blog, completely independent of CurePSP.
The single blog post so far is mixed in with news items related to CurePSP’s activities. Each item is labeled “News” or “Blog” (in the small pink ovals at the bottom). Of course, both should be of interest to the same readers.
Here’s a screen shot of the page. The first blog post is the second from the left.
In response to a commenter’s question on how zebrafish became an experimental model: Zebrafish have been systematically used in research since the 1950s, starting with studies of the causes of birth defects. The original reasons for choosing that species were that it takes only four days from fertilization to hatching and that the eggs develop outside the mother’s body. The latter makes it easy to expose the developing embryos to experimental toxins by simply adding them to the water. Even after only a week post-hatching, young zebrafish half a centimeter long display most of the physiological and behavioral features of adults 6-8 times that size. Juvenile zebrafish are transparent, allowing many experimental outcomes to be easily observed without harming the animal or further interfering in its function. Besides, they’re easy to clone as a genetically uniform colony and react to toxins in ways very similar to mammals. Much of the earliest research in developing zebrafish as a genetic model was performed in the 1960s to 80s by George Streisinger, a Holocaust survivor working at the University of Oregon. Here’s a great biosketch.
My post from two weeks ago, entitled, “A big little fish,” was about zebrafish as an experimental model for PSP. This creature, once the normal human tau gene has been added to its genome, is uniquely suited for efficiently screening long lists of drugs as treatment for tauopathies. I specifically cited a publication screening 147 currently available drugs modulating the attachment of phosphate groups or other regulators of tau production. It yielded two reasonable candidates for further research in other animal models or in people with PSP.
This week, there’s another important finding in zebrafish, except that it concerns not tau production, but tau disposal.
A research group at the University of Cambridge led by Drs. Ana Lopez, Angeleen Fleming and David Rubinsztein used zebrafish with the normal human tau gene to screen 1,437 compounds for use against tauopathies. All had been either FDA-approved for medical use or found in clinical trials to be safe, even if ineffective for whatever they were being tested for.
Next, they tested those 1,437 for the ability to improve the survival of a set of cells in the fishes’ eyes (the rods) that normally produce the tau protein. Of the 71 passing that test, the researchers chose the 16 that seemed easiest to study further. Of those, the most effective at rescuing cells from degenerating was the drug methocarbamol, which is available by prescription for muscle spasms under the brand name “Robaxin.” One of the several actions of methocarbamol unrelated to muscle relaxation is inhibition of an enzyme called carbonic anhydrase, which regulates the acid-base balance of cells.
Drugs that specifically inhibit carbonic anhydrase are available for use in glaucoma and in a variety of neurological disorders. Three of the most popular anhydrase inhibitors are acetazolamide (brand name Diamox), methazolamide (Neptazane) and dorzolamide (Trusopt). To determine if carbonic anhydrase inhibition explains the benefit of methocarbamol in the zebrafish, the researchers gave those three drugs to a different colony of zebrafish with a human tau gene, but in this case the human gene carried a mutation called P301L, which causes a rare, hereditary, PSP-like illness.
To the Cambridge team’s delight and ours, all three carbonic anhydrase inhibitors provided major protection against the damage caused by that tau gene mutation. A further set of experiments showed that the mechanism of protection was that the drugs work by improving the export of tau from the cells by the lysosomes. Those are organelles that perform part of our cells’ complicated garbage disposal mechanism.
I’ll let the researchers’ own words describe the overall results:
Together, our results suggest that CA [carbonic anhydrase] inhibition ultimately regulates lysosomal acidification and cellular distribution, promoting lysosomal exocytosis and tau secretion. This mechanism lowers tau levels within neurons, which, in turn, have lower levels of hyperphosphorylated and aggregated toxic tau forms, accounting for an improvement in phenotypic, neuronal loss and behavioral defects in vivo in zebrafish and mouse models. This raises the possibility of rapid repurposing of CA inhibitors for tauopathies, as our studies were performed in mice at human-like plasma concentrations. Furthermore, our data suggest that stimulation of unconventional secretion may also be a potent therapeutic approach for other neurodegenerative diseases caused by toxic, aggregate-prone intracellular proteins.
So, the “elevator explanation” is that carbonic anhydrase inhibitors make the fluid in lysosomes more acidic, enhancing their ability to load up on abnormal tau protein and dump it out of the brain cell.
This finding could lead to repurposing existing, off-patent carbonic anhydrase inhibitor drugs not only for PSP but potentially also for the many other neurodegenerative diseases that rely on the lysosomes to dispose of abnormal, misfolded proteins. Let’s hope that other animal models confirm this and that a clinical trial follows.
All the carbonic anhydrase inhibitors available are off patent, which means that their manufacturers would not be interested in investing the many millions of dollars needed to test them for a new use. But drug companies have been known to reformulate old drugs into longer-acting or better-absorbed versions, or to make inconsequential but patentable tweaks to old drugs’ chemical structure. Or maybe a deep-pocketed, non-commercial funder such as the NIH could fund a clinical trial of an existing carbonic anhydrase inhibitor.
So, that’s what should happen . . . and here’s what should not happen: For you to doctor-shop until you find one willing to prescribe a carbonic anhydrase inhibitor. For one thing, those drugs come with a long list of possible side effects and drug interactions. For another, it would be difficult to know if it’s working to slow the rate progression in you as an individual. If you go on a potentially neuroprotective drug and develop some moderate side effect, the decision to continue or discontinue the drug would depend on its benefit in you specifically, not on its effect in zebrafish or even in other people with PSP averaged together. That’s why drug trials observe each participant for a whole year and involve hundreds of participants randomized to experimental drug or placebo. We need faster and cheaper ways to do such trials and a lot of work is addressing that problem right now.
Meanwhile, don’t give up hope — or give in to the temptation of unproven, unmeasurable treatment.
A support group leader in Florida just sent me his notes from a presentation by an occupational therapist. She made some sensible safety recommendations that I had not heard before, so I’m passing them along to you:
Increase the lumens of light bulbs around the house, especially in the bathroom, kitchen and stairways, three frequent locations for falls.
Despite the need for better light, glare from overhead lighting or a window can impair visual performance. So, use window treatments to diffuse direct sunlight, use shades on bare bulbs and consider multiple task lighting units in strategic locations instead of a single, bright fixture.
Use night lights controlled by a motion sensor. These are available with battery power, so that they can be placed anywhere.
If you don’t have carpet on your stairway, attach a tread with a reflective strip on each step and different-appearing ones on the top and bottom landings.
Some walkers are available with floor lighting.
To ease the task of locating food on the plate, use plates that contrast with that specific meal’s food.
Remove loose rugs from bathroom floors. To avoid slipping on wet spots, try stiff, rubber mats that stick to the floor.
Grab bars in and around the shower/tub and toilet are an obvious thing, but make sure they’re installed into studs.
Use grab bars with suction cups in temporary situations such as travel.
Toilet safety rails that rest on the floor allow safer landings onto the seat and easier liftoffs, especially if paired with a seat riser.
A bidet is a good idea if you have trouble wiping. Many models can be installed in a few minutes (according to the manufacturer) by someone with no plumbing skills.
Keep in mind that this is not a complete list – just a few things that I had not seen or written about before. Www.curepsp.org has lots more advice on optimizing daily activities, including pamphlets and videos.
I also hasten to add that no list of tips is a substitute for a consultation with an occupational therapist with follow-ups as your symptoms evolve over time. If you can’t find one and your doctor doesn’t know one, just call the OT department in your nearest good hospital for recommendations.
It’s high time I updated you on currently – or imminently – recruiting PSP clinical trials.
Here are the four in chronological order. All these are for “neuroprotection,” meaning slowing of the underlying disease process. They don’t attempt to improve the existing symptoms, however. That’s called “symptomatic” treatment and I’ll get around to that soon.
More details:
Sodium selenate provides supplemental selenium, which is critical for the function of 25 human enzymes with a wide range of functions. Two are relevant to PSP: glutathione peroxidase 4 and protein phosphatase 2A. The first regulates one type of programmed cell death and the second removes phosphate groups abnormally attached to the tau protein. The trial is happening only in Australia. See here for details, including contact information.
FNP-223 inhibits an enzyme called 0-GlcNAcase (pronounced “oh-GLIK-nuh-kaze”), which removes an unusual sugar molecule from its attachment to tau. The sugar is called N-acetyl-glucosamine and it prevents abnormal tau from attaching at the same spots on the tau molecule. It’s an oral tablet and the trial, which has just started, will be in both Europe and North America. Click here for details and contact info.
AMX-0035 is a mixture of two drugs in an oral solution. Both are currently marketed for conditions unrelated to neurodegeneration. The PSP trial has started in North America and will do so in Europe and probably Japan in the next few months. One of the two drugs, called sodium phenylbutyrate (marked as Buphenyl), addresses the brain cells’ management of abnormal proteins. The other, taurursodeoxycholic acid, marketed as TUDCA, helps maintain the mitochondria. Click here for details and contact info.
Finally, GV-1001 is an enzyme with anti-inflammatory action in the brain. But it’s not like a steroid or non-steroidal anti-inflammatory drug. It acts by an mechanism that the drug company is keeping close to its chest and has something to do with DNA transcription into proteins. The drug has to be injected subcutaneously every day, like insulin. A small trial is in progress in South Korea and in you live there, here’s enrollment info. There are plans to start a trial in the US in 2025, but that could depend on the current trial’s outcome.
Soon, I’ll post something on neuroprotection trials in which the double-blind recruitment is over but the results are pending. After that will be symptomatic trials.
With all these trials in progress, CurePSP’s “Hope Matters” tagline is truer than ever.
I’ve not posted much in a while. Lots of other commitments, but unlike this blog, they had deadlines, you see. So, I have lots to catch you up on, starting with a cool study in zebrafish. This cute, 1-2-inch fishy is a popular aquarium pet. As it turns out, it also makes a great animal model for PSP.
The model is created by injecting a normal human tau gene into a fertilized fish ovum. Human tau comes in six different versions, called isoforms. The tau gene used here encodes only the single isoform that accumulates in the neurofibrillary tangles of typical, non-hereditary PSP, called 0N4R tau. The resulting adult fish not only swims poorly — its eyes don’t move very well, either. It can then be bred to form an ongoing colony. Compared with mice, the leading PSP model until now, zebrafish are cheaper and easier to maintain and provide a much more efficient way to screen dozens of drugs quickly.
The figures below are from a new publication from the University of Pittsburgh led by senior author Dr. Edward A. Burton with first author Dr. Qing Bai.
Panel A shows still images from a video of a zebrafish as seen from above. The large, dark ovals are eyes and the smudge toward the bottom is the body. Panel B shows the movements of the eyes when shown a moving array of black-and-white stripes. The blue tracing is from a fish without the added human tau gene. Its eyes move crisply from one stripe to the next, but the red tracing, from a fish with the human tau gene, shows a weak response. This is identical to the response in people with PSP who are asked by a neurologist to count the stripes on a strip of cloth moved across their field of vision. It’s called “opticokinetic nystagmus” and is a good way to detect the earliest, asymptomatic involvement of the eye movements of PSP or some other disorders.
If you go to the link provided above and scroll down to the link for “Supplementary movie 1,” you’ll see a video of the eye movements and the stimulus stripes.
Armed with this experimental set-up and another to trace traced the fish’s spontaneous swimming in a circular dish, Drs. Bai and colleagues then screened a panel of 147 chemical compounds for any ability to correct the problems. The 147 were chosen because of their ability to modulate the attachment of small molecules to genes, one type of “epigenetic” alteration that we know occurs in PSP. Large drug screens in vertebrates are much more easily performed in zebrafish than in mice.
The graph below shows the results. Each circle is one drug and the vertical axis is the improvement or worsening it produces in the zebrafish. The “whiskers” on each circle indicate the variation among the 12 fish tested on that drug. The drugs’ results are displayed left-to-right in descending order of benefit, which means that the drugs on the right, below the “0” line, were actually deleterious. The black square labeled “sibling” indicates a littermate fish without the human tau against which the drugs’ effects are compared. The red square labeled “tau” shows another kind of comparators — the fish with human tau that were left untreated. The dotted, horizontal lines are placed at a point three standard deviations (σ) from the average (μ) of the 147 drugs’ degree of benefit (upper line) or worsening (lower line). That’s the researchers’ threshold of significant interest for the drugs.
The best-performing drug was something with the weird name, (+)-JQ1. It’s a member of a group called “bromodomain inhibitors,” which have nothing to do with the element bromine. A bromodomain is a string of 110 amino acids that forms part of many proteins involved in regulating the transcription of certain genes into their own proteins. Other inhibitors of bromodomain-containing proteins are being tested as treatment for various cancers. My clinicaltrial.gov search on “bromodomain inhibitor” produced 52 such trials, though none so far for (+)-JQ1 itself. The second-best bromotomain inhibitor emerging from the zebrafish screen is trichostatin-A, a non-FDA-approved, anti-fungal antibiotic with potential anti-cancer properties and 137 listings in clinicaltrials.gov. Third is 2,4-OPD, on which I found no information anywhere.
Bonus fact for the real science nerds: The graph shows a green data point for (-)-JQ1. That’s the “enantiomer” of (+)-JQ1. Enantiomers are pairs of molecules with identical sets of atoms in mirror-image configurations. Some such pairs have identical properties but many don’t. A good example of the latter is levodopa, the (-) version of dihydroxyphenylalanine. It helps Parkinson’s dramatically and PSP modestly, but the (+) version, which would be called “dextrodopa,” does neither. The “dextro-” and “levo-” prefixes refer to the clockwise or counterclockwise rotation that a solution of the compound imparts to the plane of polarized light.
So, let’s await experiments of (+)-JQ1 and trichostatin-A in other models such as tau knock-in mice, stem cells and organoids. Let’s also await screens of other classes of drugs in the cute little zebrafish that provide a great new, efficient test bed for PSP treatments.
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