Finally, an article in the press that’s not a hit piece on Cassava

Cassava Biosciences has had the worst press imaginable with hit pieces in the Wall Street Journal, Science magazine, the New Yorker and the New York Times.  Finally Nature News has a balanced article showing how the shorts have been attacking the company and its drug — https://www.nature.com/articles/d41586-023-00050-z.

I’d written about this before and that post can be found after the ***

The Nature article discusses concerns by Elizabeth McNally editor of the Journal of Clinical Investigation, that journals are being manipulated by short sellers claiming that an article is fraudulent.

“Typically, when a whistle-blower contacts a journal about concerns over manipulated images or otherwise questionable data, the allegations are taken on good faith, McNally told Nature. The idea that whistle-blowers could be doing this for their own financial gain “was very eye-opening to me”, she says.”

One particular criticism of Cassava found in the Nature article is rather amusing. “Amid the allegations about Cassava’s data, researchers have expressed concern over how Simufilam works. Aside from the preliminary studies by Cassava and its collaborators, the strategy of stablilizing filamin-A to tackle Alzheimer’s hasn’t been on anyone’s radar, says George Perry, an Alzheimer’s researcher at the University of Texas at San Antonio. “The fact that it hasn’t been widely studied means that it hasn’t been confirmed.”

The fact that filamin-A hasn’t been on anyone’s radar is actually in its favor, since aBeta, the great white whale of Alzheimer’s research has been impaled with multiple expensive harpoons, with minimal benefit to patients.

The Nature article notes that some of the FDA petitioners wanted the Simulfilam studies stopped, something any drug company with a competing product for Alzheimer’s might wish, but should never ask for.

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The copy of this post was changed to respond to the valid criticisms of Dr. Elizabeth Bik.

 

Cassava shorts should be worried

Yesterday, 1 November ’22, a blockbuster  article was published in the Journal of Clinical Investigation (JCI) written by its editor Elizabeth McNally — https://www.jci.org/articles/view/166176.

It is just over a year ago since the first of the articles attacking Cassava Sciences appeared.  The first was in the New Yorker which profiled Jordan Thomas as the second coming of Christ for exposing supposed fraudulent data published by Cassava principals —

Radden Keefe P. The Bounty Hunter. The New Yorker. Updated January 17, 2022. Accessed October 11, 2022. https://www.newyorker.com/magazine/2022/01/24/jordan-thomas-army-of-whistle-blowers.

There were similar articles in Science — 2022;377(6604):358–363

and the New York Times https://www.nytimes.com/2022/04/18/health/alzheimers-cassava-simufilam.html.

They relied on the same assertions given to the FDA asking that the clinical trials be stopped because of ‘danger’ to the patients.

It’s worth reading McNally’s article completely.  It isn’t very long.

A few highlights (“the Journal” refers to the JCI)

“Throughout 2022, the Journal has been repeatedly contacted to comment on the 2012 JCI paper. Although we cannot be certain, there now appear to be new “short and distorters.” A recent round of emails was sent simultaneously to multiple journals and editors, identifying 25 articles with potential problems and providing recommendations on how the journals should respond. Importantly, these accusatory emails do not identify any financial conflicts of interest on the part of the whistleblowers. The emails insist that an investigation begin within 24 hours and request that the journals update them on investigative progress. As an editor, I am expressing concern because this represents a new means of manipulating the scientific publishing industry.”

So journal editors are like docs. They talk to each other to find out what’s really going on.  It is likely that McNally called up other journal editors to find out if her experience was common.

Here is why those sending the eMails should not sleep well of a night.

“Last, if the Journal uncovers allegations made for the purposes of stock manipulation, with evidence of misinformation, the JCI may elect to express its concern to the US Securities and Exchange Commission or the Department of Justice.”

It’s about time.

Whether the ‘whistle-blowers’ are guilty of anything will be determined by the suits (from investors losing money on Cassava, or perhaps Cassava itself) which are almost sure to follow.

As some of you know, I think Cassava’s data is even better than they realize. Be warned the following link is long, detailed and will require your concentration  — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/

Amyloid Structure At Last ! 4 Polymorphs

Henry J. Heinz claimed to have 57 varieties of pickles in 1896, but Cell [ vol. 184 pp. 4857 – 4873 ’21  ] Page 4862 claims that 24 amyloid polymorphs of alpha-synuclein have been found and structurally characterized.

What does this actually mean in English? The previous 3 articles in this series have discussed the structure of amyloid — the most relevant being https://luysii.wordpress.com/2021/10/11/amyloid-structure-at-last/

Basically, in amyloid some of the protein backbone flattens out so it lies in a single plane, and thousands of the planes stack on top of each other producing the amyloid fiber.  In the case of alpha-synuclein some 56 of the 144 amino acids comprising the protein flatten out.   Just as throwing a chain with 56 links on the floor will give different conformations of the chain,  the conformation of alpha-synuclein is different in each of the polymorphs.

So what?

Well, different polymorphs of another protein, the tau protein which forms the neurofibrillary tangle in Alzheimer’s give rise to at least 25 clinically distinct neurological diseases called tauopathies (3 more are chronic traumatic encephalopathy, corticobasal degeneration, and Pick’s disease).  In each of the these four diseases, a different conformation of tau is seen.

Then Nature [ vol. 598,  pp. 359 – 363 ’21] blows the field wide open, finding 19 different conformations of tau in clinically distinct diseases. Each clinical disease appears to be associated with a distinct polymorphism.  This is also true for the polymorphisms of alpha-synuclein, with distinct conformations being seen in each of Parkinsonism, multiple system atrophy and Lewy body dementia.

In none of the above diseases is there a mutation (change in amino acid sequence) in the protein

Back to alpha-synuclein.  How did they get the 24 different conformations?  They incubated the protein under different conditions (e.g. different salt concentrations, different alpha-synuclein concentrations, different salts).

Why is this incredibly good news? 

Because it moves us past amyloid itself, to the conditions which cause amyloid to form.  Certainly, removing amyloid or attacking it hasn’t resulted in any clinical benefit for the Alzheimer patient despite billions being spent by Big Pharma to do so.

We will start to study the ‘root causes’ of amyloid formation.   The amino acid sequence of each protein is identical despite the different conformations of the chain in the amyloid. Clearly the causes must be different for each of the different polymorphs of the protein.  This just has to be true.

Some cynic said that people who talk about the root causes of crime never get their hands dirty.  Hopefully neuroscience is about to take off its gloves.

This is why alternative approaches to Alzheimer’s disease, such as Cassava Biosciences manipulation of filamin A, might bear fruit.   For details please see — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

Just got this back from one of the authors of the Nature paper

“Yes, studying the conditions that lead to all these different structures
is certainly high on our to-do list now.”

 

More moonlighting

Well we used to think we understood what ion channels in the cell membrane did and how they worked. To a significant extent we do know how they conduct ions, permitting some and keeping others out in response to changes in membrane potential and neurotransmitters. It’s when they start doing other things that we begin to realize that we’re not in Kansas anymore.

Abnormal binding of one protein (filamin A) to one of the classic ion channels (the alpha7 nicotinic cholinergic receptor) may actually lead to a therapy for Alzheimer’s disease — for details please see — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

The Kv3.3 voltage gating potassium channel is widely expressed in the brain.  Large amounts are found neurons concerned with sound, where firing rates are high.  Kv3.3 repolarizes them (and quickly) so they can fire again in response to high frequency stimuli (e.g. sound).  Kv3.3 is also found in the cerebellum and a mutation Glycine #529 –> Arginine is associated with a hereditary disease causing incoordination (type 13 spinocerebellar ataxia or SCA13 to be exact).

Amazingly the mutant conducts potassium ions quite normally.  The mutation (G529R) causes the channel not to bind to something called Arp2/3 with the result that actin (a muscle protein but found in just about every cell in the body) doesn’t form the network it usually does  at the synapse.  Synapses don’t work normally when this happens. 

Why abnormally functioning synapses isn’t lethal is anyone’s guess, as is why the mutation only affects the cerebellum.  So it’s another function of an ion channel, completely unrelated to its ability to conduct ions (e.g. moonlighting). 

The science behind Cassava Sciences (SAVA)

I certainly hope Cassava Sciences new drug Simufilam for Alzheimer’s disease works for several reasons

l. It represents a new approach to Alzheimer’s not involving getting rid of the plaque which has failed miserably

2. The disease is terrible and I’ve watched it destroy patients, family members and friends

3. I’ve known one of the principals (Lindsay Burns) of Cassava since she was a teenager and success couldn’t happen to a nicer person. For details please see https://luysii.wordpress.com/2021/02/02/montana-girl-does-good-real-good/.

Unfortunately even if Sumifilam works I doubt that it will be widely used because of the side effects (unknown at present) it is very likely to cause.  I certainly hope I’m wrong.

Here is the science behind the drug.  We’ll start with the protein the drug is supposed to affect — filamin A, a very large protein (2,603 amino acids to be exact).  I’ve known about it for years because it crosslinks actin in muscle, and I read everything I could about it, starting back in the day when I ran a muscular dystrophy clinic in Montana.  

Filamin binds actin by its amino terminal domain.  It forms a dimerization domain at its carboxy terminal end.  In between are 23 repeats of 96 amino acids which resemble immunoglobulin — forming a rod 800 Angstroms long.  The dimer forms a V with the actin binding domain at the two tips of the V, making it clear how it could link actin filaments together. 

Immunoglobulins are good at binding things and Lindsay knows of 90 different proteins filamin A binds to.  This is an enormous potential source of trouble.  

As one might imagine, filamin A could have a lot of conformations in addition to the V, and the pictures shown in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099194/.

One such altered (from the V) conformation binds to the alpha7 nicotinic cholinergic receptor on the surface of neurons and Toll-Like Receptor 4 (TLR4) inside the cell.

Abeta42, the toxic peptide, has been known for years to bind tightly to the alpha7 nicotinic receptor — they say in the femtoMolar (10^-15 Molar) range, although I have my doubts as to whether such tiny concentration values are meaningful.  Let’s just say the binding is tight. 

The altered conformation of filamin A makes the binding of Abeta to alpha7even tighter. 

In some way, the tight binding causes signaling inside the cell (mechanism unspecified) to hyperphosphorylate the tau protein, which is more directly correlated with dementia in Alzheimer’s disease than the number of senile plaques. 

So what does Sumifilam actually do — it changes the ‘altered’ conformation of filamin A back to normal, decreasing Abeta signaling inside the cell.  

How do they know the conformation of filamin A has changed?  They haven’t done cryoEM or Xray crystallography on the protein.  The only evidence for a change in conformation, is a change in the electrophoretic mobility (which is pretty good evidence, but I’d like to know what conformation is changed to what).

Notice just how radical this proposed mechanism of action actually is.  The nicotinic cholinergic receptor is an ion channel, yet somehow the effect of Sumifilam is on how the channel binds to another protein, rather than how it conducts ions. 

However they have obtained some decent results with the drug in a very carefully done (though small — 13 patients) study in J. Prev Alz. Dis. 2020 (http://dx.doi.org/10.14283/ipad2020.6) and the FDA this year has given the company the go ahead for a larger phase III trial.

Addendum 26 March: The above link didn’t work.  This one should — it’s from Lindsay herself

https://link.springer.com/article/10.14283/jpad.2020.6

Why, despite rooting for the company and Lindsay am I doubtful that the drug will find wide use.  We are altering the conformation of a protein which interacts with at least 90 other proteins (Lindsay Burns, Personal Communication).  It seems inconceivable that there won’t be other effects in the neuron (or elsewhere in the body) due to changes in the interaction with the other 89 proteins filaminA interacts with.  Some of them are likely to be toxic.