6 ms·

Parents of kids with rare disease found a promising drug

74 points by shawndumas 11y ago

refurb 11y ago
Fantastically little information provided, yet it's called a "breakthrough!!". How is the drug dosed? If it's oral, then I'm not surprised. It probably traps the cholesterol in the mouse-model diet before it can even be absorbed.
- aaronbrethorst 11y ago
  FTA: They found cyclodextrin and initially tried using it in oral doses, which is known to be safe. However, the chemical couldn’t effectively reach the brain that way. The couple made headlines with their tireless efforts to get drug companies, the FDA, and doctors to let them try out intravenous treatments of cyclodextrin for their twins—and they won. Regular treatments gradually improved—although didn’t cure—the twins’ conditions. Cyclodextrin is now in clinical trials to treat other kids with NPC.
  - dekhn 11y ago
    This interesting approach just raises more questions than it answers; experiments with sample size n=1 being run by non-medically trained individuals are unorthodox and generally suspect in the modern medical climate.
    - aaronbrethorst 11y ago
      here's another experiment for you that I've run on myself: When I consume products that contain wheat, I feel sick. When I don't, I feel fine. Sample size n=1, and I am not medically trained. What conclusions, if any, do you think I can draw from my experience?
      - actaeon169 11y ago
        Clearly, I need to stop eating wheat.
      - dekhn 11y ago
        I don't know, did you control for placebo effects? Did you verify there isn't something else in those products that makes you feel sick? Science is hard. Control experiments are key.
jrapdx3 11y ago
Article certainly piques my curiosity, unfortunately the paywall it's behind impedes getting the whole story. How often have we seen "breakthroughs" fail to live up to expectations, in this case not yet enough info to have any idea how it's likely to turn out. An interesting side-note here is that cholesterol itself has "detergent-like" properties similar to the cyclodextrin agent. That is, both molecules have hydrophilic and hydrophobic ends, which enables stabilizing lipid droplets floating in an aqueous medium like the bloodstream. I suppose cyclodextrin properties will vary with molecular weight and conformation, but never would have guessed it would have the basic characteristics described. Always amazes me where discoveries come from, goes to show it isn't always high-cost, specialized research that leads the way.
dnautics 11y ago
This is amazing. The unfortunate thing though is that the effectiveness of cyclodextrin on NPC (versus atherosclerosis) might not hold up to scrutiny - I remember the NPC finding when it first came out almost a decade ago (worked in a lab that was interested in NPC) but more recent experiments have thrown the result into question. It's kind of strange that this hasn't been proposed before - when you buy cholesterol for scientific experiments, it's often encapsulated in cyclodextrin, that product has been around for a while. [edit:] found this http://www.tandfonline.com/doi/abs/10.1080/10717540050120205#.VwbYtSZyhyQ http://www.tandfonline.com/doi/abs/10.1080/10717540050120205... so someone has investigated it before, at least.
kazinator 11y ago
> Typical treatments include statins and other cholesterol-lowering drugs, which are not always effective, particularly when patients don’t adhere to doctor-prescribed, low-cholesterol diets. Must an otherwise good article perpetuate the tired bullshit about dietary cholesterol. A piece of white bread topped with sugary jam (optionally on top of margarine) is a low-cholesterol snack. Just because cholesterol shows up from what you ate doesn't mean that, say, statins aren't working; maybe you're just throwing off the method by which their effectiveness is indirectly gauged.
- atomical 11y ago
  Please provide sources that dietary cholesterol has no impact.
  - beagle3 11y ago
    See e.g. http://chriskresser.com/the-diet-heart-myth-cholesterol-and-saturated-fat-are-not-the-enemy/ http://chriskresser.com/the-diet-heart-myth-cholesterol-and-... and the references therein. Also, read https://en.wikipedia.org/wiki/Phytosterol#Cholesterol_lowering https://en.wikipedia.org/wiki/Phytosterol#Cholesterol_loweri... Dietary cholesterol seems to have a minor (~10%) impact on serum cholesterol levels, and no impact on CVD or all cause mortality. And this has been known (and ignored) IIRC for about 40 years now. Cholesterol is a symptom of problems, not their cause. Note, however, that this is regarding a typical human. There are rare genetic diseases in which cholesterol itself is the culprit. I have no knowledge of this specific disease, but it might be one of them.
- pygy_ 11y ago
  I know it doesn't have an impact in healthy people, but what about people with hypercholesterolemia? I don't know if it is the case, but it sounds plausible that the drugs that regulate endogenous production like statins would only be effective in the absence of an external supply (since they don't affect the way cholesterolemia is regulated).
  - pygy_ 11y ago
aab0 11y ago
Beware surrogates. An apropos bit of news from a few days ago: http://www.nytimes.com/2016/04/04/health/dashing-hopes-study-shows-cholesterol-drug-has-no-benefits.html http://www.nytimes.com/2016/04/04/health/dashing-hopes-study... http://blogs.sciencemag.org/pipeline/archives/2016/04/04/cetp-finally-heads-to-the-trash-heap http://blogs.sciencemag.org/pipeline/archives/2016/04/04/cet... Cyclodextrin may be useful for Niemann-Pick disease, where the cholesterol itself is the immediate proximate cause of the problem, but if it's already clinically-approved and has been used, where are the heart attack correlations?
- sndean 11y ago
  > but if it's already clinically-approved and has been used, where are the heart attack correlations? This is what I'd like to know. I'm not a formulation chemist, but we should see differing outcomes related to different formulations. Maybe someone switched to PEG and saw worse outcomes for this reason? I'd also be interested to see what happens with different substitutions on CD.
- mathgeek 11y ago
  > but if it's already clinically-approved and has been used, where are the heart attack correlations? I read is as being used currently, but the "breakthrough" being administration through IV. I'm not sure if that's correct, was just my interpretation.

74 points by shawndumas 11y ago

Fantastically little information provided, yet it's called a "breakthrough!!". How is the drug dosed? If it's oral, then I'm not surprised. It probably traps the cholesterol in the mouse-model diet before it can even be absorbed.

aaronbrethorst 11y ago
FTA: They found cyclodextrin and initially tried using it in oral doses, which is known to be safe. However, the chemical couldn’t effectively reach the brain that way. The couple made headlines with their tireless efforts to get drug companies, the FDA, and doctors to let them try out intravenous treatments of cyclodextrin for their twins—and they won. Regular treatments gradually improved—although didn’t cure—the twins’ conditions. Cyclodextrin is now in clinical trials to treat other kids with NPC.
- dekhn 11y ago
  This interesting approach just raises more questions than it answers; experiments with sample size n=1 being run by non-medically trained individuals are unorthodox and generally suspect in the modern medical climate.
  - aaronbrethorst 11y ago
    here's another experiment for you that I've run on myself: When I consume products that contain wheat, I feel sick. When I don't, I feel fine. Sample size n=1, and I am not medically trained. What conclusions, if any, do you think I can draw from my experience?
    - actaeon169 11y ago
      Clearly, I need to stop eating wheat.
    - dekhn 11y ago
      I don't know, did you control for placebo effects? Did you verify there isn't something else in those products that makes you feel sick? Science is hard. Control experiments are key.

jrapdx3 11y ago

Article certainly piques my curiosity, unfortunately the paywall it's behind impedes getting the whole story. How often have we seen "breakthroughs" fail to live up to expectations, in this case not yet enough info to have any idea how it's likely to turn out. An interesting side-note here is that cholesterol itself has "detergent-like" properties similar to the cyclodextrin agent. That is, both molecules have hydrophilic and hydrophobic ends, which enables stabilizing lipid droplets floating in an aqueous medium like the bloodstream. I suppose cyclodextrin properties will vary with molecular weight and conformation, but never would have guessed it would have the basic characteristics described. Always amazes me where discoveries come from, goes to show it isn't always high-cost, specialized research that leads the way.

dnautics 11y ago

This is amazing. The unfortunate thing though is that the effectiveness of cyclodextrin on NPC (versus atherosclerosis) might not hold up to scrutiny - I remember the NPC finding when it first came out almost a decade ago (worked in a lab that was interested in NPC) but more recent experiments have thrown the result into question. It's kind of strange that this hasn't been proposed before - when you buy cholesterol for scientific experiments, it's often encapsulated in cyclodextrin, that product has been around for a while. [edit:] found this http://www.tandfonline.com/doi/abs/10.1080/10717540050120205#.VwbYtSZyhyQ http://www.tandfonline.com/doi/abs/10.1080/10717540050120205... so someone has investigated it before, at least.

kazinator 11y ago

> Typical treatments include statins and other cholesterol-lowering drugs, which are not always effective, particularly when patients don’t adhere to doctor-prescribed, low-cholesterol diets. Must an otherwise good article perpetuate the tired bullshit about dietary cholesterol. A piece of white bread topped with sugary jam (optionally on top of margarine) is a low-cholesterol snack. Just because cholesterol shows up from what you ate doesn't mean that, say, statins aren't working; maybe you're just throwing off the method by which their effectiveness is indirectly gauged.

atomical 11y ago
Please provide sources that dietary cholesterol has no impact.
- beagle3 11y ago
  See e.g. http://chriskresser.com/the-diet-heart-myth-cholesterol-and-saturated-fat-are-not-the-enemy/ http://chriskresser.com/the-diet-heart-myth-cholesterol-and-... and the references therein. Also, read https://en.wikipedia.org/wiki/Phytosterol#Cholesterol_lowering https://en.wikipedia.org/wiki/Phytosterol#Cholesterol_loweri... Dietary cholesterol seems to have a minor (~10%) impact on serum cholesterol levels, and no impact on CVD or all cause mortality. And this has been known (and ignored) IIRC for about 40 years now. Cholesterol is a symptom of problems, not their cause. Note, however, that this is regarding a typical human. There are rare genetic diseases in which cholesterol itself is the culprit. I have no knowledge of this specific disease, but it might be one of them.
pygy_ 11y ago
I know it doesn't have an impact in healthy people, but what about people with hypercholesterolemia? I don't know if it is the case, but it sounds plausible that the drugs that regulate endogenous production like statins would only be effective in the absence of an external supply (since they don't affect the way cholesterolemia is regulated).
- pygy_ 11y ago

aab0 11y ago

Beware surrogates. An apropos bit of news from a few days ago: http://www.nytimes.com/2016/04/04/health/dashing-hopes-study-shows-cholesterol-drug-has-no-benefits.html http://www.nytimes.com/2016/04/04/health/dashing-hopes-study... http://blogs.sciencemag.org/pipeline/archives/2016/04/04/cetp-finally-heads-to-the-trash-heap http://blogs.sciencemag.org/pipeline/archives/2016/04/04/cet... Cyclodextrin may be useful for Niemann-Pick disease, where the cholesterol itself is the immediate proximate cause of the problem, but if it's already clinically-approved and has been used, where are the heart attack correlations?

sndean 11y ago
> but if it's already clinically-approved and has been used, where are the heart attack correlations? This is what I'd like to know. I'm not a formulation chemist, but we should see differing outcomes related to different formulations. Maybe someone switched to PEG and saw worse outcomes for this reason? I'd also be interested to see what happens with different substitutions on CD.
mathgeek 11y ago
> but if it's already clinically-approved and has been used, where are the heart attack correlations? I read is as being used currently, but the "breakthrough" being administration through IV. I'm not sure if that's correct, was just my interpretation.