Under the "Who'da thought?" category, put this news about cyclodextrin. For those outside the field, that's a ring of glucose molecules, strung end to end like a necklace. (Three-dimensionally, it's a lot more like a thick-cut onion ring - see that link for a picture). The most common form, beta-cyclodextrin, has seven glucoses. That structure gives it some interesting properties - the polar hydroxy groups are mostly around the edges and outside surface, while the inside is more friendly to less water-soluble molecules. It's a longtime additive in drug formulations for just that purpose - there are many, many examples known of molecules that fit into the middle of a cyclodextrin in aqueous solution.
But as this story at the Wall Street Journal shows, it's not inert. A group studying possible therapies for Niemann-Pick C disease (a defect in cholesterol storage and handling) was going about this the usual way - one group of animals was getting the proposed therapy, while the other was just getting the drug vehicle. But this time, the vehicle group showed equivalent improvement to the drug-treatment group.
Now, most of the time that happens when neither of them worked; that'll give you equivalence all right. But in this case, both groups showed real improvement. Further study showed that the cyclodextrin derivative used in the dosing vehicle was the active agent. And that's doubly surprising, since one of the big effects seen was on cholesterol accumulation in the central neurons of the rodents. It's hard to imagine that a molecule as big (and as polar-surfaced) as cyclodextrin could cross into the brain, but it's also hard to see how you could have these effects without that happening. It's still an open question - see that PLoS One paper link for a series of hypotheses. One way or another, this will provide a lot of leads and new understanding in this field:
Although the means by which CD exerts its beneficial effects in NPC disease are not understood, the outcome of CD treatment is clearly remarkable. It leads to delay in onset of clinical signs, a significant increase in lifespan, a reduction in cholesterol and ganglioside accumulation in neurons, reduced neurodegeneration, and normalization of markers for both autophagy and neuro-inflammation. Understanding the mechanism of action for CD will not only provide key insights into the cholesterol and GSL dysregulatory events in NPC disease and related disorders, but may also lead to a better understanding of homeostatic regulation of these molecules within normal neurons. Furthermore, elucidating the role of CD in amelioration of NPC disease will likely assist in development of new therapeutic options for this and other fatal lysosomal disorders.
Meanwhile, the key role of cholesterol in the envelope of HIV has led to the use of cyclodextrin as a possible antiretroviral. This looks like a very fortunate intersection of a wide-ranging, important biomolecule (cholesterol) with a widely studied, well-tolerated complexing agent for it (cyclodextrin). It'll be fun to watch how all this plays out. . .