An Alzheimer's Cure? Not So Fast. - Corante

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October 11, 2013

An Alzheimer's Cure? Not So Fast.

Posted by Derek

The British press (and to a lesser extent, the US one) was full of reports the other day about some startling breakthrough in Alzheimer's research. We could certainly use one, but is this it? What would an Alzheimer's breakthrough look like, anyway?

Given the complexity of the disease, and the difficulty of extrapolating from its putative animal models, I think that the only way you can be sure that there's been a breakthrough in Alzheimer's is when you see things happening in human clinical trials. Until then, things are interesting, or suggestive, or opening up new possibilities, what have you. But in this disease, breakthroughs happen in humans.

This latest news is nowhere close. That's not to say it's not very interesting - it certainly is, and it doesn't deserve the backlash it'll get from the eye-rolling headlines the press wrote for it. The paper that started^[3] all this hype looked at mice infected with a prion disease^[4] , which led inexorably to neurodegeneration and death. They seem to have significantly slowed that degenerative cascade (details below), and that really is a significant result. The mechanism behind this, the "unfolded protein response"^[5] (UPR) could well be general enough to benefit a number of misfolded-protein diseases, which include Alzheimer's, Parkinson's, and Huntington's, among others. (If you don't have access to the paper, this^[6] is a good summary).

The UPR, which is a highly conserved pathway, senses an accumulation of misfolded proteins inside the endoplasmic reticulum. If you want to set it off, just expose the cells you're studying to Brefeldin A^[7] ; that's its mechanism. The UPR has two main components: a shutdown of translation (and thus further protein synthesis), and an increase in chaperones to try to get the folding pathways back on track. (If neither of these do the trick, things will eventually shunt over to apoptosis, so the UPR can be seen as an attempt to avoid having the apoptotic detonator switch set off too often.

Shutting down translation causes cell cycle arrest, as well it might, and there's a lot of evidence that it's mediated by PERK, the Protein kinase RNA-like Endoplasmic Reticulum Kinase. The team that reported this latest result had previously shown^[8] that two different genetic manipulations of this pathway could mediate prion disease in what I think is the exact same animal model. If you missed the wild excited headlines when that one came out, well, you're not alone - I don't remember there being any. Is it that when something comes along that involves treatment with a small molecule, it looks more real? We medicinal chemists should take our compliments where we can get them.

That is the difference between that earlier paper and this new one. It uses a small-molecule PERK inhibitor (GSK2606414^[9] ), whose discovery and SAR is detailed here^[10] . And this pharmacological PERK inhibition recapitulated the siRNA and gain-of-function experiments very well. Treated mice did show some behavioralthis really does look quite solid, and establishes the whole PERK end of the UPR as a very interesting field to work in.

The problem is, getting a PERK inhibitor to perform in humans will not be easy. That GSK inhibitor, unfortunately, has side effects that killed it as a development compound. PERK also seems to be a key component of insulin secretion^[11] , and in this latest study, the team did indeed see elevated blood glucose and pronounced weight loss, to the point that that treated mice eventually had to be sacrificed. Frustratingly, PERK inhibition might actually be a target to treat ^[12] insulin resistance in peripheral tissue, so if you could just keep an inhibitor out of the pancreas, you might be in business. Good luck with that. I can't imagine how you'd do it.

But there may well be other targets in the PERK-driven pathways that are better arranged for us, and that, I'd think, is where the research is going to swing next. This is a very interesting field, with a lot of promise. But those headlines! First of all, prion disease is not exactly a solid model for Alzheimer's or Parkinson's. Since this pathway works all the way back at the stage of protein misfolding, it might be just the thing to uncover the similarities in the clinic, but that remains to be proven in human trials. There are a lot of things that could go wrong, many of which we probably don't even realize yet. And as just detailed above, the specific inhibitor being used here is strictly a tool compound all the way - there's no way it can go into humans, as some of the news stories got around to mentioning in later paragraphs. Figuring out something that can is going to take significant amount of effort, and many years of work. Headlines may be in short supply along the way.

Comments (20) + TrackBacks (0) | Category: Press Coverage | The Central Nervous System^{[13] [14] [15] [16]}

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RELATED ENTRIES

› An Alzheimer's Cure? Not So Fast.^[17]

› Unpacking a JACS Total Synthesis Paper^[18]

› Cambridge Meetup Final Plans: Noon by Broad Canal Way^[19]

› A Leak at Lilly^[20]

› Ariad's Ponatinib Runs Into Big Trouble^[21]

› The 2013 Nobel Prize in Chemistry^[22]

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› Did the Biotech IPO Window Just Close?^[24]

References

1. ^{^} « Unpacking a JACS Total Synthesis Paper (pipeline.corante.com)


2. ^{^} Main (pipeline.corante.com)


3. ^{^} The paper that started (stm.sciencemag.org)


4. ^{^} prion disease (www.cdc.gov)


5. ^{^} "unfolded protein response" (en.wikipedia.org)


6. ^{^} this (www.cureffi.org)


7. ^{^} Brefeldin A (en.wikipedia.org)


8. ^{^} had previously shown (www.ncbi.nlm.nih.gov)


9. ^{^} GSK2606414 (en.wikipedia.org)


10. ^{^} here (pubs.acs.org)


11. ^{^} key component of insulin secretion (www.jbc.org)


12. ^{^} target to treat (www.ncbi.nlm.nih.gov)


13. ^{^} Comments (20) (pipeline.corante.com)


14. ^{^} TrackBacks (0) (pipeline.corante.com)


15. ^{^} Press Coverage (pipeline.corante.com)


16. ^{^} The Central Nervous System (pipeline.corante.com)


17. ^{^} An Alzheimer's Cure? Not So Fast. (pipeline.corante.com)


18. ^{^} Unpacking a JACS Total Synthesis Paper (pipeline.corante.com)


19. ^{^} Cambridge Meetup Final Plans: Noon by Broad Canal Way (pipeline.corante.com)


20. ^{^} A Leak at Lilly (pipeline.corante.com)


21. ^{^} Ariad's Ponatinib Runs Into Big Trouble (pipeline.corante.com)


22. ^{^} The 2013 Nobel Prize in Chemistry (pipeline.corante.com)


23. ^{^} 36 Basic Types of Reactions? (pipeline.corante.com)


24. ^{^} Did the Biotech IPO Window Just Close? (pipeline.corante.com)