A development in amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) may have welcome implications for PSP.

A tiny drug company based in Blue Bell, PA called Mitochon Pharmaceuticals just announced having won a $1 million grant from the ALS Association to mount a Phase II, double-blind trial of their drug in ALS.  The company expects the trial to kick off in early 2027, with a six-month double-blind period.  That means that the result should be available in late 2028 (my own optimistic estimate). 

The drug, known as MP-101 or 2,4-dinitrophenol, is given as an oral capsule and exerts multiple actions in the brain.  Chief among these is to correct leaks in the membrane enclosing the mitochondria, the cells’ power plants where sugar and oxygen come together to produce energy.  PSP has a similar problem with its own mitochondria.  While it’s not as important in PSP as in ALS, it’s possible that neutralizing one important such issue could have a calming effect on the whole self-reinforcing cycle of damage. That’s why Mitochon is interested in testing MP-101 in PSP as well. But so far, they have been unable to raise financing for a PSP trial and have no other drugs on the market to provide that capital.

What probably swayed the ALS Association in deciding to support the Phase II trial was spinal fluid results from Mitochon’s much smaller (10 patients) and shorter (2 weeks) ALS trial, where MP-101 reduced levels of neurofilament light chain (NfL).  That’s a protein released into the spinal fluid and blood in multiple conditions involving rapid loss of axons connecting brain cells, including those in PSP.  While the NfL level, therefore, is a diagnostic marker and not part of the problem itself, it holds promise as a sensitive way to detect benefit from an experimental drug.  Demonstrating such an effect would require far fewer patients and/or dollars than relying on any imaging procedure or neuro exam result. 

There are other biological similarities between ALS and PSP despite the fact that ALS is mostly a disease of the spinal cord and PSP is mostly a disease of the basal ganglia and brainstem:

• Aggregates of the protein TDP-43, the equivalent of the tau aggregates of PSP, occur in the spinal cord in nearly half of all people with PSP, often in the same set of cells as in ALS.
• Both diseases include important defects in the brain cells “garbage disposal” systems.
• Both have problems coordinating the transport of vesicles around the cell.  Those are tiny bubbles of membrane with chemicals that are made in one part of the cell but needed elsewhere.
• Inflammation is important in both, and in both ALS and PSP it involves the microglia, which are the “white blood cells” of the brain and spinal cord.
• The first and most important genetic risk factor in PSP, called the tau H1 haplotype, is also associated with ALS despite the fact that the latter is not a tau-based disorder.  (The same is true for Parkinson’s disease.)
• Both diseases can involve the frontal cortex, producing “executive dysfunction” as a cognitive symptom.

Here’s what I hope: 

• I hope that MP-101 will be spectacularly successful in slowing the progression of ALS, which is just as disabling as PSP but starts 20 years younger, on average, and is fatal after an average of only three years.
• I hope that funders with pockets as deep as those of the ALS Association will take a cue from that fine organization and fund a trial of MP-101 in PSP. 

For the scientists among you, here’s Mitochon’s brief but technical explanation of the mechanism of action of MP-101, lightly edited by me:

MP101 is a mitochondrial uncoupler, 2,4-dinitrophenol (DNP), a weak acid with a dissociable proton. The pharmacology of MP101 is unique in that it involves a transfer of proton (H+) into the pH-basic mitochondrial matrix, a non-genomic event. This event involves: 1) lowering damage by reducing ROS production and calcium overload, while 2) promoting repair with the induction of cAMP production, activation of CREB and production of BDNF.

For a far more detailed review by John Geisler, PhD, co-founder and chief scientific officer of Mitochon, see this link. As you’ll read, Dr. Geisler has more ambitions for the drug than just ALS and PSP.

Disclosure: I have consulted for Mitochon in the past but have never had, and do not have, a financial interest in the success of the company.