Tag Archives: Alzheimer’s

A neurodegenerative panacea? Maybe so!

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In a reply to a commenter back in July 2022, I expressed pessimism about the neuroprotective potential of buntanetap, formerly known as posiphen.  That drug is claimed to reduce genetic transcription of multiple neurodegeneration (NDD)-related proteins, including tau, at the messenger RNA (mRNA) level.  I thought it unlikely that one drug could do that without impairing production of other proteins necessary to health and life. 

Later in the same year, 2022, a double-blind trial of buntanetap in Parkinson’s disease and Alzheimer’s disease was published. The N was small, with 54 participants with PD and 14 with AD.   The treatment period was very short, only 25 days, which means that any result would reflect only symptomatic, not neuroprotective (disease-slowing), effects. That’s because the progression of PD and AD are too slow to be measured over only a 25-day period.  However, the main purpose of the trial was to study safety and tolerability, not efficacy.  The trial also checked spinal fluid levels of multiple proteins associated with the diseases – i.e., biomarkers.

The result were small but statistically significant improvement in some of the cognitive and motor measures in PD and some of cognitive measures in AD.  Most of the biomarkers showed improvement, but none were statistically significant.

Some cell/molecular biology here, folks: The authors argue that previous attempts to treat NDDs by targeting only one protein at a time have failed because all the diseases actually include defects in multiple proteins.  They point out that the mRNAs of multiple NDD-related proteins and iron-metabolizing proteins share a section called an iron-responsive element (IRE).  But the mRNA for the iron-metabolizing proteins is very slightly different from that for the NDDs. IREs are not translated into any part of its parent protein, but they do regulate that protein’s production by the ribosomes: When the level of iron in the cell is too high, the IRE prevents the ribosomes from making the protein. The butanetap molecule binds to a specific part of the IRE, mimicking a high-iron effect.  Luckily, the drug does not bind to mRNA of actual iron-metabolizing proteins – only to that of NDD-related proteins.   

So, if you skipped that nerd interlude, the executive summary is that there’s a good scientific rationale for why buntanetap could work.

But there are some potential issues with the 2022 clinical trial:

  • Many of the patients experienced minor side effects such as headache, rash or muscle spasms.  This could have impaired the blinding scheme and produced a placebo effect.  That issue could have been addressed by asking the patients at study’s end, before the randomization assignments were revealed, whether they thought they had been on placebo or active drug. 
  • Some of the spinal fluid markers that improved related to neuro-inflammation.That, and the improvement in the NDD-related markers, would not have been directly caused by a placebo effect. However, the increased mobility resulting from a placebo effect might have reduced neuro-inflammation, reducing in turn the markers of brain tissue damage.  (Only the patients with PD, not AD, received testing for physical mobility and there was no record of the patients’ exercise habits.) 
  • Like many drug trials at this early stage, this one was not only sponsored by the drug company, but the first and last authors were company employees.  I found no evidence of dishonesty in reading the paper, but a potential financial and professional conflict-of-interest does exist.
  • As stated, this trial was only 25 days long, and we really need to know the longer-term side effects of depriving the brain of a whole raft of normal proteins, even if some of those molecules later cause mischief.

Enough for now.  My next post will discuss the results of a larger, more recent trial of buntanetap that has not yet been published in a peer-reviewed journal.  Cliffhanger.

One RNA fits all?

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Maybe I’m streaming too many dramatic TV series these days.  My October 9 post ended in a cliffhanger, teasing an “oddball” molecule that could point the way to neuroprotective treatments for PSP and other neurodegenerative diseases. It’s called “lncRNA FAM151B-DT.” 

Quickly, some background.  The RNA most familiar to us is messenger RNA.  Its length can be anywhere from a few hundred to a few thousand base pairs (the genetic code’s “letters” for a single gene or a fragment thereof). The RNA is constructed (“transcribed”) in the cell’s nucleus from the code in DNA, then scoots out to the ribosomes, where it’s translated into a string of amino acids to build a specific protein.  But only about two percent of the DNA in our genome encodes the kind of RNA for making proteins, called messenger RNA.  Most of the rest, about 75 to 90 percent, encodes RNA that regulates DNA transcription or other cell functions.  A little of that “non-coding RNA” is “micro-RNA,” which has only about 20 to 25 base pairs, and the rest, with over 200 base pairs, is called “long, non-coding RNA.” 

Now I’ll get to the point. A research group at Washington University in St. Louis just published a paper entitled, “A novel lncRNA FAM151B-DT regulates degradation of aggregation prone proteins.”  They used brain cells obtained at autopsy from people who had died with PSP, Alzheimer’s, or Parkinson’s disease.  They also used skin cells from a living person with a form of frontotemporal dementia with Parkinsonism (FTDP), which is caused by a mutation in the tau gene. They transformed those (slightly) specialized skin cells into unspecialized stem cells, then transformed those into highly specialized brain cells.

The lead author of the WashU study is Arun Renganathan, PhD, a staff scientist in the Department of Psychiatry.  The senior author is Celeste Karch, PhD, associate professor of psychiatry. Disclosure: Dr. Karch and I have collaborated in research in the past and she’s a member of CurePSP’s Scientific Advisory Board, which I am honored to chair.

In each of those four disease-specific brain cell cultures, the team found FAM151B-DT reduced relative to control cells and that silencing FAM151B-DT by “knocking out” its gene increased the concentration of whichever protein was aggregating in the corresponding human disease (tau for PSP, AD and FTD-P; alpha-synuclein for PD). The mechanism was a blockage of autophagy, an important component of brain cells’ “garbage disposal” system.  The researchers found that FAM151B-DT serves as a “scaffold” to allow the tau or alpha-synuclein protein and a “chaperone” molecule called HSC70 to interact with the lysosomes, a kind of bubble in the cell fluid containing protein-degrading enzymes.  

A critical piece of the new research is that increasing the cells’ production of FAM151B-DT stimulated that system to dispose of excess tau or alpha-synuclein. That means that FAM151B-DT is the “rate-limiting step” in the process.  As you’d imagine, this suggests that increasing the concentration or efficiency of FAM151B-DT could slow or halt progression of these diseases.  All four of them.

So, how does this relate to the cliffhanger from yesterday’s post about our evolving perspective on the similarities and differences between PSP and AD?  One reason to be interested in the differences between those two is that a rare disease with limited research funding like PSP could benefit from research on treatments for AD, a very common disease with much more research funding and huge commercial potential.  Besides, we in the PSP community like when drug companies try out their AD drugs on PSP first – because of their common underlying cellular and biochemical similarities. The new paper from WashU has found one more very important similarity.

It’s not only PSP and AD.  The new paper found FAM151B-DT just as relevant to PD and FTDP.  I expect to see research soon on its relevance to others forms of FTD and to ALS, dementia with Lewy bodies, corticobasal degeneration, multiple system atrophy, and many others.  Then we wouldn’t have to worry so much about making an accurate diagnosis early in the disease course– maybe one cure will fit all!