FDA considers first CRISPR gene editing treatment that may cure sickle cell
cnn.com
cnn.com
That being said, I do want to clarify that this isn't a "cure" for sickle cell disease. It is not editing the gene causing sickle cell itself, but rather allowing for increasing production of HbF (fetal hemoglobin) by knocking down a suppressor. Hydroxyurea, a current standard of care option in sickle cell disease, also increases HbF production but response can be variable among patients (but when it works, absolutely improves quality of life!)
In addition, I think we always need to keep in mind potential toxicities and hopefully, we learn more about this when the publication actually comes out. It's important to note that giving this therapy requires giving high dose chemotherapy beforehand, and I'd also be interested in knowing how long this therapy actually lasts as I do expect the product may wane with time.
But still, so excited to see CRISPR technology coming to the public and the potential for this technology in many different disease states!
I honestly don’t know, but qualifying as a “cure” doesn’t require fixing the original thing that was broken.
Whether something is classified as a cure or treatment just depends on the extent and permanence of its effectiveness.
Is that not what’s happening here?
But I think in this case they're right to clarify. I think the low level of common knowledge around gene editing could lead people to believe that this is mutating the sickle cells into healthy cells, which it isn't doing
Usually curing would mean fixing the problem, or more specifically it would mean permanently eliminating the symptoms. This contrasts with "treatment" temporarily relieving the symptoms.
https://my.clevelandclinic.org/health/articles/24434-cure
> Being cured of a disease means it’s completely gone and isn’t coming back. For many people, cures represent the ultimate treatment goal. Most diseases and conditions aren’t curable.
(This link disagrees with my use of "treatment", saying that "treatment" is any procedure, and "cure" is one of many possible outcomes of a treatment, with temporary relief being another possible outcome. But the point stands that curing definitely does mean fixing the problem.)
Glasses do not cure myopia, but they are so effective at relieving the symptoms, in an inexpensive and noninvasive way, that there is no real need for a cure.
No, I believe you’re thinking of “problem” in a different way.
A cure permanently relieves symptoms of a disease. The symptoms are what’s “gone and is never coming back.”
That much alone is called a “functional cure”, it’s not just a treatment.
The difference between a cure and a functional cure depends on the disease but in either case, it means it’s not coming back.
> A cure permanently relieves symptoms of a disease.
This is a surreal correction for you to make after selectively quoting the first half of my sentence. Let's look at the whole thing:
>> Usually curing would mean fixing the problem, or more specifically it would mean permanently eliminating the symptoms.
Did you have something to add to that?
In that sense AIDS is also cured, but in my book it's not, because people with it have to take pills for the rest of their lives and those pills do have serious side effects.
In your example the question would be, does antiretroviral therapy cure HIV? It does reduce the viral load but not permanently, so no, its not considered a cure.
The answer might change with the treatment. Does a stem cell bone marrow transplant eliminate HIV? Yes, permanently as far as it’s known so HIV is “cured” in this case.
So it's a cure for some definitions of cure, but not all
The language around "cure" is complicated in general. We often use it in diseases like cancer but with modern therapies, we do have some patients on long-term therapy making their cancer more of a chronic one - are they cured? On the other hand, we rarely use the word cure with diseases like hypertension or diabetes which can devastating diseases in their own right but can be controlled effectively with medication.
So yes, what should really matter is the actual outcomes - are people living longer? Is their quality of life better? And, with exa-cel/Casgevy, the latter is absolutely true (and the first will be known after time).
Cure means gone. That’s why Cancer people talk about remission. I’m old enough to remember the talk around curing cancer and then it came back and killed people the medical community walked it back.
This means most people on the planet I think. You could just take a malaria pill.
It is debilitating and affects a lot of their everyday life. I’m really happy this is progressing.
https://thescholarship.ecu.edu/handle/10342/3137
You can purchase it from many places but this manufacturer has a good reputation:
BULKSUPPLEMENTS.COM L-Citrulline Malate 2:1 Powder - L Citrulline Malate Supplement, Citrulline Malate Powder - Unflavored & Gluten Free - 3g per Servings, 333 Servings, 1kg (2.2 lbs) https://a.co/d/fzNovRX
Citrulline is extremely safe in any quantity. Any excess is urinated out.
Best I can tell that’s because you used the word SUPPLEMENTS in all caps which is reminiscent of spam email.
However, while I can’t validate anything about your grandfather what you’re saying seems plausible and some papers have talked about it.
His patents were exhaustively written and documented in medical textbook style (rather than legal robot style) further detailing the variety of uses of citrulline:
https://patents.google.com/patent/US5874471A/en
The essence is arginine is crucial in the production of NO, which serves many functions of the body but it’s also a powerful vasoprotector. Sickle cell is popularly thought to cause anemia due to the cell shape not carrying enough oxygen, but in fact it’s due to the shape irritating the epithelial cells lining blood vessels, particularly small vessels and capillaries. This redirects the use of arginine in the body to repairing and protecting the blood vessels in the body.
Citrulline is an intermediate non essential amino acid found in high concentration in watermelon seeds (hence the name). It survives the gut, unlike direct arginine ingestion, and converts readily to arginine in the kidneys (my grandfather was an expert in kidney function and pioneered kidney transplants in the 1950’s and 1969’s, his interest in sickle came late in his career in the 1990’s).
He was also an expert in heart disease, and as a young man was a tenured professor of medicine at University of Kentucky, chair of cardiovascular research, and an endowed member of the Kentucky Heart Association. He left Kentucky to found the first regional hospital and medical school in eastern North Carolina, ECU, where he was the director for many years. He was a terror of grad students, never accepted outside grant money for any of his research, never worked with drug companies, and led the bioethical research boards at his medical school for most of his career. He earned the nickname Dr House for his remarkable ability to diagnose obscure diseases and conditions along with novel treatments using his encyclopedic knowledge of biochemistry and disease, as well as his often obnoxious personality. The university forced him to retire because he brought no funding and had an entire floor for his lab when he was in his late 70’s, so he tore out his garage and built a laboratory in its place where he spent the rest of his years self publishing new research.
https://www.legacy.com/us/obituaries/reflector/name/william-...
You can say express your empathy and care without it being compromised.
(not a commentary on your parent comment)
What I find interesting is there is some cultural tension around how much to discourage such public displays. Donations can do good even if the gift giver is simply trying to improve their image. Ex: "Beware of practicing your piety before others in order to be seen by them; for then you have no reward from your Father in heaven. So whenever you give alms, do not sound a trumpet before you, as the hypocrites do in the synagogues and in the streets, so that they may be praised by others. Truly I tell you, they have received their reward.“ Notice how there’s zero implication that the behavior is negative and even an acknowledgment that doing so brings rewards, just the suggestion that it’s just not pious.
There’s many things you can take from the crucifixion, but part of the message is being crucified is fatal. And you’re like obviously, but being obvious doesn’t mean something is false.
The irony of this statement seems to be lost on you.
I think their concern is whether the public healthcare system will actually cover the cost. I think they should and will. Certainly cheaper than all the other treatments over the course of their lifetime.
I think it’s possible folks may protest against it for cost reasons but also for the eugenics-slippery-slope argument. I hope that doesn’t happen.
I assume it's a long and labour-intensive process?
But it's a cure, not a treatment.
As more people become proficient at this treatment, the cost will come down. But to truly get it down to reasonable amount will require automation, and we're a long way off from automating crispr.
Plus gene therapy is in its infancy, so everything here is going to be novel and expensive. Novel treatments generally have a limited audience with even fewer practitioners, so you can't spread the R&D costs across many patients.
Prices will go down with time as patents expire and competitors emerge and this line of treatment (perhaps) becomes mainline, but that's on a ~20 year timeframe.
Everything about this is bespoke (each treatment is based on the individual cells of a patient) and artisanal (the process requires a highly skilled individual to complete), and run by a guild (only so many people are allowed to run gene therapy trials).
On the other hand, since this is a cure, and probably reduces long-term medical care costs, it could very well actually be "cheaper" in the long run, which incentivizes the government to treat as many people as possible.
However, the technology, techniques and equipment developed to automate the process have massively cut costs and increased speed over that time.
> A new speed record in DNA sequencing may soon help families more quickly find answers to difficult and life-altering questions.
In just 7 hours, 18 minutes, a team of researchers at Stanford Medicine went from collecting a blood sample to offering a disease diagnosis. This unprecedented turnaround time is the result of ultra-rapid DNA sequencing technology paired with massive cloud storage and computing.
https://www.asbmb.org/asbmb-today/science/022722/record-brea...
You have to crawl before you can run.
[1] https://customercare.23andme.com/hc/en-us/articles/212196868...
The research and the approval are extremely expensive and risky. Without a boatload of cash at the end of the tunnel, nobody would do it.
Patents will expire and in a generation, this will become cheap.
https://www.england.nhs.uk/2023/02/first-baby-receives-life-...
I'm not arguing this is true, but I wouldn't accept a counterargument based on "but it's people, it's people, think of the children"
- Most formal drug research, today, is already not worthwhile. The norm is that you spend several billion dollars and recover nothing.
- Most achievements that were worthwhile in retrospect were not worthwhile prospectively. Therefore it is not obvious that things need to be worthwhile prospectively in order to be done. Going into a career as a rock star is, objectively, stupid. But we have a huge supply of wannabe rock stars anyway.
For example, Hemgenix is a gene therapy for hemophilia. It is a single-dose product priced at $3.5 million [1]. It's not CRISPR-based, so it's not an apples-to-apples comparison with the sickle-cell treatment discussed in the article. But I know from officials at the World Federation of Hemophilia that the direct costs of production and administration for Hemgenix are around $50,000. That's two orders of magnitude less than the list price.
The $3.5 million figure was likely arrived at because the existing products for hemophilia cost north of 350k annually, and Hemgenix is estimated to replace them for 8+ years.
[1]https://www.scientificamerican.com/article/3-5-million-hemop...
That doesn't account for the R&D effort which has to be recouped during the runtime of the patent. Depending on whom you ask, that can reach into billions of dollars [1], and there's just about 200k people diagnosed with some form of hemophilia of which only a fraction has the funds or the insurance to obtain that kind of treatment in the first place (both the current and the new one), so these few patients have to account for the R&D cost of the medication, the R&D cost of failed candidate substances, the R&D for ongoing other medication and profits. For "orphan diseases", these economies are a serious problem.
Pharmaceutical development is incredibly expensive; to make it worse a lot of governments have cut back drastically on fundamental R&D grants for universities and so private companies with their profit interests stepped in.
[1] https://msf-access.medium.com/how-much-do-clinical-trials-co...
[2] https://www.pfizer.com/disease-and-conditions/hemophilia
> there's just about 200k people diagnosed with some form of hemophilia of which only a fraction has the funds or the insurance to obtain that kind of treatment in the first place (both the current and the new one)
This was actually the crux of the discussion where I learned about the $50k figure. There are a lot of hemophiliacs in countries that spend, on average, just a few hundred dollars per capita each year on health care. Even if Hemgenix went royalty-free right away and no one ever turned a dollar of profit on it, gene-therapy cures are still inaccessible to the bulk of people the World Federation of Hemophilia represents.
$3.5 million would be like landing on the moon, and $0.05 million would be like a few orbits at ISS height, but they're both astronomical. They're equally out of reach for most people with severe hemophilia.
It seems more likely they would just, uh, collect a sample of a single sperm cell and treat that, then use it with a treated egg using IVF.
Genuine question: why? Isn't the argument against germ-line editing one for diversity? If so, it seems fine to have some populations who ban it while others experiment with it.
However, when you suffer all your life from a genetic disease such as, say, the sickle cell or diabetes type 1, it is very obvious that it is any delay or hinderance in this direction that is deeply unethical, not the practice. Your germ line gets hundreds of random mutations at every conception, and your gamets get tons more mutations and errors as you age. It's not a dynasty hairloom.
https://www.wired.com/story/a-single-infusion-of-a-gene-edit...
> 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/
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/ I'm optimistic about this.
> 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/
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.
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
...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...
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-...
I don't know why I'm being asked to explicitly state that.
Infection: "not a good thing."
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.
I encourage you to reflect on your prior statements.
> I'm leery of any claim that "this one neat trick will be the end of this entire class of disease."
Sure, I overspoke. My usage of the word eliminate is strong - there are always edge cases in biology. And I should've been more specific with my language and specified ASCVD instead of the more broad "heart disease". That would, kinda by definition, scope what I'm talking about to fatty deposits. However, I think we're deep in pedantic territory and I hope you forgive me my excess. I didn't mean to enter "one neat trick' territory, though I can see how I came off that way.
> chagas
I'm also a layman and accept there are gaping holes in my knowledge, which is why I asked you a genuine question: "What do you suggest is the mechanism of action behind that?". My interpretation is that high levels of chronic inflammation leads to endothelial damage which leads to the formation of cholesterol plaques as the immune system attempts to fix the damage it caused. I'm going to assume here that "Infection chewing on the heart is a problem." means you think the parasite literally eats holes in blood vessels? I don't know what you think, which is why I asked. If you know the pathogenesis of heart disease with Chagas, I'd love to learn.
> I am leery of any plan to globally suppress any class of molecule.
A fair concern. I would note that healthy children have an LDL of 23.8 mg/dl https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529694/ and they manage to supply their greedy brains. Note too that circulating (blood) cholesterol is not "global" cholesterol:
> The body has four distinct “pools” of cholesterol, in which tissues have regulatory mechanisms to maintain their respective homeostasis. In order of size, these pools of cholesterol consist of: peripheral tissues, red blood cells, liver, and lipoproteins. It turns out that the brain synthesizes its own cholesterol and does not exchange cholesterol with the other aforementioned pools, which means that cholesterol concentrations outside the brain have no direct impact on brain cholesterol. https://peterattiamd.com/does-low-cholesterol-cause-cognitiv...
I'm not readily finding an explanation for how CRISPR works that makes sense to me and the current top comment* indicates this isn't actually a cure. I was hoping to get some idea of how CRISPR and a virus delivery mechanism compare.
The DNA testing should be mandatory for everyone, but let parents decide for themselves if they want a child with an incurable disease. Maybe we should make them pay extra taxes if they ignore the warning.
According to Wiki: "Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene (HBB) that makes haemoglobin, one from each parent". So basically this disease is encoded in DNA and it can be predicted whether future child will inherit it. Mandatory DNA screening could result in zero people having this disease (and other expensive to treat or incurable diseases). There will be no need to spend large money researching it, and those money can be used for more important non-genetic diseases.
Of course, religious people would be against this but we as a society should rely on science, not on blind faith.
You trust the government to decide who can and can't reproduce? You see no problem with this?
You see no room for abuse here?
There's already tests to show parents many diseases detected early on. It's just not mandatory to terminate.
What tests are you talking about that should be done BEFORE conception!?
Supporting a test that says you have X gene and that might result in a problem so you can't reproduce is a ridiculous stance to have.
You seem to have no knowledge about current medical screenings and no regard for human liberty.
DNA test that detects errors (invalid sequences) known to cause serious illnesses. I think everyone who is considering to have children, should take such a test because he or she can be a carrier of invalid DNA which can be inherited and ruin life for a child. People should behave responsibly.
I wonder why no one ever thought to implement such a thing?
I would rethink that if I were you.
According to Wiki, "Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene (HBB) that makes haemoglobin, one from each parent". So this is a disease caused by errors in DNA sequence and it can be predicted whether the child will have it.
One of those ends with millions of people in camps. I'll let you think about which one it is.
With the right preparation and equipment, it could be a highschool science class project.
malaria is an interesting one where multiple antimalarials have been developed and then lost efficacy.
In America
* About 1 in 13 black babies are born with sickle cell trait.
* About 1 in every 365 black babies are born with sickle cell disease.
* People who come from Hispanic, Southern European, Middle Eastern, or Asian Indian backgrounds can also have sickle cell disease.
* Of the 74 817 hospitalized for sickle cell disease (2016 to 2018), 69 889 (93.4%) were Blacks, 3603 (4.8%) were Hispanics, and 1325 (1.8%) were Whites.