But presenilin 1 is a promising drug target if it is really the mysterious gamma secretase.
It turns out gamma secretase plays a role in regulating cell growth in the intestines.
Or it might be hitting its proper target (the enzyme gamma secretase) but in too blunt a fashion.
The compound may have interfered with other essential functions of gamma secretase that have nothing to do with amyloid.
Her conclusion years ago: Gamma secretase inhibitors like the Lilly drug would block presenilin and hence might make things worse.
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Her experiments suggest that blocking the protein hit by gamma secretase will kill brain cells over the long term.
According to Dr. Steve Gardell, who led the teams, these scientists created a chemical to which they knew gamma secretase would bind.
Researchers in Iceland identified a rare genetic mutation that slows the activity of an enzyme called beta secretase, which is required to produce amyloid-beta.
The Lilly and Elan scientists figured that by blocking gamma secretase, an enzyme responsible for creating the amyloid fragments, they might halt amyloid production itself.
Indeed, a group of Harvard scientists will also publish a paper identifying presenilin 1 as gamma secretase in the July issue of Nature Cell Biology.
Do you think there is a safety issue with other gamma secretase inhibitors going forward in testing, such as the one Bristol-Myers Squibb is testing?
Soon after the Elan deal ended, Lilly's chemists made a few tweaks and devised a new secretase blocker that showed fewer side effects in animals.
It may be there was something bad about this compound, or it may be that blocking the gamma secretase enzyme is not a good approach.
By this point Eli Lilly had resurrected its gamma-secretase program.
Scientists named the slasher gamma secretase, but this is about the same as calling an unknown serial killer "Jack the Ripper" or "The Unabomber" and drawing a composite sketch.
Lilly is testing its gamma-secretase inhibitor on 1, 500 patients.
But if the toxic effects were caused directly by the intended effect of the drug (blocking gamma secretase), that would raise serious questions as to whether it is safe to continue with other trials of gamma secretase drugs now ongoing at other drug companies including Bristol-Myers Squibb.
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