3 ms·

We could eliminate heart disease, which is still the number 1 killer of men, women, in the US, and globally. https://www.wired.com/story/a-single-infusion-of-a

We could eliminate heart disease, which is still the number 1 killer of men, women, in the US, and globally. https://www.wired.com/story/a-single-infusion-of-a-gene-editing-treatment-lowered-high-cholesterol/ https://www.wired.com/story/a-single-infusion-of-a-gene-edit...

deleted 3y ago
[deleted]
sxg 3y ago
That trial was specifically for familial types of hypercholesterolemia, which are strongly genetic. Not clear that it would also work for run-of-the-mill high cholesterol, although it is possible.
- AlexErrant 3y ago
  Fair point. I subscribe to the idea that LDL causes heart disease: > Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel https://pubmed.ncbi.nlm.nih.gov/28444290/ https://pubmed.ncbi.nlm.nih.gov/28444290/ The trial inhibited PCSK9, and this study says "other PCSK9 mutations result in unusually low concentrations of plasma LDL cholesterol and a reduced risk of atherosclerotic disease". https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079795/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079795/ I'm optimistic about this.
  - DoreenMichele 3y ago
    There are other things that also cause heart disease.
    - AlexErrant 3y ago
      As far as I know, ApoB is the only "necessary but not sufficient" molecule, and that's mostly in LDL. There's also IDL and VLDL, but AFAIK those are in insufficient quantities to have clinical significance - please LMK if you know otherwise. There's also Lp(a), but PCSK9 inhibitors also work there: > For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469722/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469722/ I hate to sound like I'm only focused on PCSK9i - there's also ezetimibe/bempedoic acid/statins, but AFAIK only PCSK9 has been shown to be a viable target of CRISPR. Perhaps that's your point, but I wonder what would happen if we flattened ApoB starting at age, say, 25. Perhaps the residual Lp(a) wouldn't be enough to cause any MACE.
      - DoreenMichele 3y ago
        It is known that infection plays a role in some cases and increasingly suspected that it is a risk factor generally. Up to 45% of people with chronic infections develop heart disease 10–30 years after the initial illness, which can lead to heart failure. https://en.m.wikipedia.org/wiki/Chagas_disease https://en.m.wikipedia.org/wiki/Chagas_disease ...gum disease can be caused by 20 to 30 different types of bacteria... and it is increasingly thought that gum disease is probably an independent risk factor for heart disease. https://www.heart.org/en/news/2021/03/19/how-oral-health-may-affect-your-heart-brain-and-risk-of-death https://www.heart.org/en/news/2021/03/19/how-oral-health-may...
        AlexErrant 3y ago
        What do you suggest is the mechanism of action behind that? I submit ApoB. Same reason why high blood pressure leads to ASCVD. Note that risk factor is not causal. I.e. not exercising is a risk factor. Notably it seems like you can't drive LDL too low https://www.health.harvard.edu/blog/ldl-cholesterol-how-low-can-you-safely-go-2020012018638 https://www.health.harvard.edu/blog/ldl-cholesterol-how-low-...
        DoreenMichele 3y ago
        Infection chewing on the heart is a problem. I don't know why I'm being asked to explicitly state that. Infection: "not a good thing."
        AlexErrant 3y ago
        ...I feel like we're on different levels so let's just stop here before you start to condescend.
        DoreenMichele 3y ago
        I'm not condescending. Chagas disease is a class of trypanosomiasis which currently the medical establishment doesn't know how to treat. It's due to a parasite. Parasites living in your heart and feeding on the tissue is not a good thing independent of whether or not it is related to fatty deposits in the vessels. I'm genuinely baffled that in a discussion of heart disease, actual infection is being handwaved off as irrelevant and only another possible means to cause fatty deposits. I'm sure our backgrounds are really different. I'm a knowledgeable layperson and a lot of people are dismissive of me because of that. It doesn't mean your "level" is somehow implicitly above mine anymore than one language is inherently "superior" to another. Language is a tool. Its purpose is communication. If one chooses language that fails to adequately communicate with the target audience, the failure is on the speaker. Let me add that while I clearly am not as well versed in fatty deposits in the circulatory system as you are, I am leery of any plan to globally suppress any class of molecule. The brain has the most cholesterol of any organ in the body. If we suppress fats globally to "prevent heart disease," what might this do to the brain? Bone marrow is fatty. It's a critical part of the immune system where white blood cells are produced. If we suppress fat globally, what does this do to our immune system? They invented antibiotics not that many decades ago and announced "the end of disease." Fast forward to today and we are wrestling with antibiotic resistant infections and drug shortages. I'm leery of any claim that "this one neat trick will be the end of this entire class of disease." In this case, I readily know of actual diseases that specific one neat trick wouldn't help at all which are pertinent to the category known as heart disease.

deleted 3y ago

[deleted]

sxg 3y ago

That trial was specifically for familial types of hypercholesterolemia, which are strongly genetic. Not clear that it would also work for run-of-the-mill high cholesterol, although it is possible.

AlexErrant 3y ago
Fair point. I subscribe to the idea that LDL causes heart disease: > Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel https://pubmed.ncbi.nlm.nih.gov/28444290/ https://pubmed.ncbi.nlm.nih.gov/28444290/ The trial inhibited PCSK9, and this study says "other PCSK9 mutations result in unusually low concentrations of plasma LDL cholesterol and a reduced risk of atherosclerotic disease". https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079795/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079795/ I'm optimistic about this.
- DoreenMichele 3y ago
  There are other things that also cause heart disease.
  - AlexErrant 3y ago
    As far as I know, ApoB is the only "necessary but not sufficient" molecule, and that's mostly in LDL. There's also IDL and VLDL, but AFAIK those are in insufficient quantities to have clinical significance - please LMK if you know otherwise. There's also Lp(a), but PCSK9 inhibitors also work there: > For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469722/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469722/ I hate to sound like I'm only focused on PCSK9i - there's also ezetimibe/bempedoic acid/statins, but AFAIK only PCSK9 has been shown to be a viable target of CRISPR. Perhaps that's your point, but I wonder what would happen if we flattened ApoB starting at age, say, 25. Perhaps the residual Lp(a) wouldn't be enough to cause any MACE.
    - DoreenMichele 3y ago
      It is known that infection plays a role in some cases and increasingly suspected that it is a risk factor generally. Up to 45% of people with chronic infections develop heart disease 10–30 years after the initial illness, which can lead to heart failure. https://en.m.wikipedia.org/wiki/Chagas_disease https://en.m.wikipedia.org/wiki/Chagas_disease ...gum disease can be caused by 20 to 30 different types of bacteria... and it is increasingly thought that gum disease is probably an independent risk factor for heart disease. https://www.heart.org/en/news/2021/03/19/how-oral-health-may-affect-your-heart-brain-and-risk-of-death https://www.heart.org/en/news/2021/03/19/how-oral-health-may...
      - AlexErrant 3y ago
        What do you suggest is the mechanism of action behind that? I submit ApoB. Same reason why high blood pressure leads to ASCVD. Note that risk factor is not causal. I.e. not exercising is a risk factor. Notably it seems like you can't drive LDL too low https://www.health.harvard.edu/blog/ldl-cholesterol-how-low-can-you-safely-go-2020012018638 https://www.health.harvard.edu/blog/ldl-cholesterol-how-low-...
        DoreenMichele 3y ago
        Infection chewing on the heart is a problem. I don't know why I'm being asked to explicitly state that. Infection: "not a good thing."
        AlexErrant 3y ago
        ...I feel like we're on different levels so let's just stop here before you start to condescend.
        DoreenMichele 3y ago
        I'm not condescending. Chagas disease is a class of trypanosomiasis which currently the medical establishment doesn't know how to treat. It's due to a parasite. Parasites living in your heart and feeding on the tissue is not a good thing independent of whether or not it is related to fatty deposits in the vessels. I'm genuinely baffled that in a discussion of heart disease, actual infection is being handwaved off as irrelevant and only another possible means to cause fatty deposits. I'm sure our backgrounds are really different. I'm a knowledgeable layperson and a lot of people are dismissive of me because of that. It doesn't mean your "level" is somehow implicitly above mine anymore than one language is inherently "superior" to another. Language is a tool. Its purpose is communication. If one chooses language that fails to adequately communicate with the target audience, the failure is on the speaker. Let me add that while I clearly am not as well versed in fatty deposits in the circulatory system as you are, I am leery of any plan to globally suppress any class of molecule. The brain has the most cholesterol of any organ in the body. If we suppress fats globally to "prevent heart disease," what might this do to the brain? Bone marrow is fatty. It's a critical part of the immune system where white blood cells are produced. If we suppress fat globally, what does this do to our immune system? They invented antibiotics not that many decades ago and announced "the end of disease." Fast forward to today and we are wrestling with antibiotic resistant infections and drug shortages. I'm leery of any claim that "this one neat trick will be the end of this entire class of disease." In this case, I readily know of actual diseases that specific one neat trick wouldn't help at all which are pertinent to the category known as heart disease.