Tag Archives: RNA

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!

Anti-sense oligo update

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CurePSP asked me to write up something on ASOs for their website (www.curepsp.org). Thought I’d give my loyal blog readers a sneak peak:

Probably the single biggest story in the world of PSP right now is NIO752.  That’s an antisense oligonucleotide (ASO) being tested for safety and tolerability in people with PSP.

ASOs interrupt the process by which a specific gene’s DNA is transcribed into RNA, thereby reducing the production of the encoded offending protein.  The ASO itself is a short stretch of RNA whose genetic code is a mirror-image of part of the DNA whose translation is to be suppressed.  The ASO’s genetic sequence and that of the offending DNA recognize each other and stick together, preventing the corresponding protein from being produced. In this case, the targeted DNA is the MAPT gene, which encodes the tau protein. Other ASOs operate by targeting slightly different stages of the transcription/translation process.

In the US, the FDA has approved several kinds of ASO, the best-known being nusinersin (brand name “Spinraza”) for spinal muscular atrophy, a progressive and usually fatal condition that typically starts in infancy but in mild forms can start at any age.  In the pivotal trial of nusinersen, 21 of 51 infants receiving the drug were improved after 6 months, while that was true for none of the 27 infants receiving sham treatment.  If we can achieve similar results for NIO752, it would be by far the best news ever for PSP.

ASO molecules are too large to cross the blood-brain barrier, which means that for a brain disease, they must be administered by injection directly into the spinal fluid.  This is performed as for a diagnostic spinal tap.  In the current trial, NIO752 is given once monthly over a period of 3 months and the participants are examined periodically for an additional 9 months.  The 64 participants are at 4 sites in the US (La Jolla, CA; Boca Raton, FL; Rochester, MN and Nashville TN), 2 in Canada (both in Montreal), 5 in Germany and 1 in the UK. This safety and tolerability trial is expected to end in May 2024.  Its sponsor is Novartis Pharmaceuticals, co-headquartered in Basel, Switzerland and Cambridge, MA. For more information: 1-888-669-6682 or novartis.email@novartis.com

A trial can detect important safety issues with only 64 participants but detecting actual benefit requires more.  The standard “primary outcome measure” for clinical treatment trials in PSP is the PSP Rating Scale.  Assuming that is still the case in 2024, when a treatment trial would begin, and half of the participants receive placebo, the minimum number of participants needed would be 276.  That number also assumes that the study is designed to detect at least a 30% difference between the two groups’ rates of progression.  Detecting less of a difference would require more participants and detecting a greater difference would require fewer.  A new outcome measure with less variability than the PSPRS would reduce the number of participants required.

From the standpoint of those with PSP and their families hoping to enter a trial of NIO752, the most important number isn’t a number, but a date: A trial starting in mid-2024 would probably end in 2027. Another important number is the eventual price of the drug.  NIO752 would have to be injected every month, lifelong. Nusinersen’s price is $125,000 per injection.  So, if the price of NIO752 is anything like that, the cost to Medicare, Medicaid and private insurors would present an impossible situation.  CurePSP estimates that about 20,000 people in the US have PSP at any given time.  If even half of them received a $125,000-per-month drug, the total annual cost would be $15 billion plus the doctors’ fees for the monthly injection procedure.  Clearly, something would have to give. 

But first, let’s hope that NIO752 actually works.