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Haemophilia A trial results 'mind-blowing'

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Re: Haemophilia A trial results 'mind-blowing'

#91

Post by Nomentatus »

openasocket wrote: post #27
sswaner wrote: post #8

There is a pretty strong argument that Haemophilia is the disease that has had the biggest impact on the last 100 years. Russian heir to the throne Alexis Romanov inherited the disease and his suffering and lack of treatment options destabilized his family and contributed to leadership issues culminating in Russian defeat in WW1 and the Russian revolution and the rise of the Soviet Union. Agree? If not, what disease…

I'd argue the Bolshevik revolution would still have happened even if Romanov wasn't a hemophiliac. I don't see how the child's disease would have affected the management of the Russian supply lines in WWI, or have caused the February Revolution.

It may have been quite helpful in fact; particularly after the invention of the telegraph, remote amateur micromanagment by royal, tyrannical and elected HIPPOs (including Hitler and even perhaps even Lincoln at the start of the war) has crippled many a military effort.

Re: Haemophilia A trial results 'mind-blowing'

#92

Post by Nomentatus »

liveoneggs wrote: post #16
sswaner wrote: post #8

There is a pretty strong argument that Haemophilia is the disease that has had the biggest impact on the last 100 years. Russian heir to the throne Alexis Romanov inherited the disease and his suffering and lack of treatment options destabilized his family and contributed to leadership issues culminating in Russian defeat in WW1 and the Russian revolution and the rise of the Soviet Union. Agree? If not, what disease…

syphilis increased the crazy of many many important people until antibiotics came into common use

Apparently it was the most common cause of death until 1946 in the US, although doctors usually didn't write "Syphilis" in death certificates for the sake of the family; just the final cause of death such as pneumonia.

Re: Haemophilia A trial results 'mind-blowing'

#93

Post by vanderZwan »

aaavl2821 wrote: post #41
test6554 wrote: post #31

This is fascinating! I wonder if something like this could get the pancreas to begin producing insulin. Type I Diabetes is no joke. It could save tens or hundreds of millions per year, not to mention multiple injections per person per day.

There are lots of people working on regenerative medicine and gene therapy for autoimmune diseases (ive worked with several researchers focused on type 1), but unfortunately the field isnt there yet. hemophilia a is a disease caused largely by deficiencies in one specific protein. massive technological breakthroughs in recent years have enabled scientists to deliver genes to human cells to consistently, accurately an…

From what I understand, autoimmune diseases are a mix of genetic predisposition and "learned behaviour" by the human immune system, i.e. some stressor making the immune system mislabeling a part of the own body as hostile. Once this is "learned", would removing the genetic predisposition even have an effect? Do we even know how the immune system "remembers" previous illnesses?

If not, gene therapy can only be applied pre-emptively, I guess, unless we somehow manage to isolate the mechanism of how measles resets the immune system, and apply it selectively to the part that has learned the autoimmune behaviour[0].

[0] http://www.sciencetimes.com/articles/6168/20150508/measles-w...

Re: Haemophilia A trial results 'mind-blowing'

#94

Post by Nomentatus »

mrfusion wrote: post #63

Could we do the same thing with sickle cell?

Since that trait can be viewed as the double-absence of the statistically "normal" gene, I would guess yes. The near normal protein levels in this trial (despite the fact that only a small percentage of cells were likely altered) are a very positive sign.

Re: Haemophilia A trial results 'mind-blowing'

#95

Post by ericb »

tialaramex wrote: post #77
ericb wrote: post #64

Earlier quoted context omitted.

Is the virus transmissible?

The study did not look at whether family members or other close acquaintances ended up containing measurable numbers of copies of the virus. The patients were tested and the study verified that the (altered) genetic data from the virus was excreted normally. The virus was deliberately defective and unable to replicate, so the copies made for use in treatment are the only copies that would ever exist. This also ensure…

Thanks for the tldr; I hadn't realized that was possible.

Re: Haemophilia A trial results 'mind-blowing'

#96

Post by carbocation »

DoreenMichele wrote: post #86
carbocation wrote: post #18

Earlier quoted context omitted.

> the microbiome is what will typically unlock those diseases or not given the gene set If true, that would be a Nobel-worthy finding. I don't think this is true, but do you have a citation supporting this for the "typical" genetic disease?

I don't think that is far-fetched. The gut contains about 70% of the cells of your immune system. I have a genetic disorder. Working on my gut health has gone a long way towards reversing my symptoms. I don't talk about it as much as I used to because it was a constant shit show from people being completely dismissive, outright calling me crazy and asserting utterly illogical things in the name of their "scientific"…

I don't think there is a relationship between your personal experience and the OP's claim that diseases, broadly, are typically mediated by the gut microbiome.

Re: Haemophilia A trial results 'mind-blowing'

#97

Post by DoreenMichele »

carbocation wrote: post #96
DoreenMichele wrote: post #86

Earlier quoted context omitted.

I don't think that is far-fetched. The gut contains about 70% of the cells of your immune system. I have a genetic disorder. Working on my gut health has gone a long way towards reversing my symptoms. I don't talk about it as much as I used to because it was a constant shit show from people being completely dismissive, outright calling me crazy and asserting utterly illogical things in the name of their "scientific"…

I don't think there is a relationship between your personal experience and the OP's claim that diseases, broadly, are typically mediated by the gut microbiome.

So explain to me how 70% of the body's immune cells being in the gut is unrelated to how diseases are typically mediated. Pretty please.

Re: Haemophilia A trial results 'mind-blowing'

#98

Post by carbocation »

will_brown wrote: post #40
carbocation wrote: post #18

Earlier quoted context omitted.

> the microbiome is what will typically unlock those diseases or not given the gene set If true, that would be a Nobel-worthy finding. I don't think this is true, but do you have a citation supporting this for the "typical" genetic disease?

Well I know without anyone reading or commenting on anything I link to I’ll be downvoted into oblivion for even trying to support conversations I’ve had with multiple physicians, still as a physician yourself I ask you to at least weigh in on the following...is it not true that while genetic mutations can be the sole cause of disease that most disease are triggered by a combination of genetics and environmental facto…

We can agree on many of the things that you wrote:

- You need a combination of genetics + environment to have a phenotype (whether disease or otherwise)

- Several conditions have a relationship with the gut microbiome

Also, I think you will enjoy this absolutely amazing study that found that the gut microbiome drives cerebral cavernous malformations(!!!) by interactions with TLR4: https://www.nature.com/articles/nature22075

So, I just don't think that "typically" the gut microbiome is the driver of disease. In fact, it's a rare enough find that people get Nature papers out of it. But, if it is actually typical, then I stand by my assertion that someone will eventually get a Nobel prize from proving it.

Re: Haemophilia A trial results 'mind-blowing'

#99

Post by aaavl2821 »

ImSkeptical wrote: post #88
aaavl2821 wrote: post #75

Earlier quoted context omitted.

hate to be the bearer of bad news, but there are something like 400+ drugs that have prevented type 1 in mice and another hundred or so that have reversed it. none have worked in people the most common animal model for type 1, the NOD mouse model, is notoriously bad. studies have shown that loud music cures diabetes in these mice. mice raised in one lab get diabetes differently than mice raised in another. the immune…

It's some kind of philosophical ethics problem that we can't experiment on humans even though there would be a net benefit. I feel like there are morally unintuitive solutions that may help - perhaps criminals of certain kinds, who have damaged society, could repay their debt, in part, by volunteering for trials we can be sure they understand. We might also leverage The suicidal by offering, after therapy, a way for…

I understand where you are coming from logically, although I am of the belief that this is not ethically acceptable. Ethics aside, jumping straight to human testing without assessing safety wouldnt really save that much in terms of cost and time to develop a drug, compared to developing better in vitro and animal models of disease

safety studies are not the largest driver of cost and duration of drug development. failing a later stage human study that assess effectiveness is a much bigger needle mover in terms of cost, as is the arduous and painstaking process of early drug discovery and development. human studies of effectiveness cost $15-500M+ and can take 3-7 years. putting a drug in humans that has a low probability of success is the most value destructive thing you can do in pharma. the other big cost driver is early research in drug discovery and development. understanding the biology and chemisty, developing assays, and screening compounds can cost $15-20M+ and take 5+ years. by comparison, animal safety studies cost maybe $5M and take a year or two

For more context:

There's an important distinction to be drawn between two main types of animal models: models assessing drug "safety", and those assessing "effectiveness". the models of effectiveness are very poor and of questionable value in some cases, although they are often the best we have. animal models of effectiveness are not literally required for FDA approval, although in reality they pretty much are

animal models of safety, however, are required by FDA, and rightly so. they are of much greater value. generally you must do studies in a small species like a mouse as well as a non-human primate. these "toxicology" studies basically entail dosing animals with huge amounts of drug, way more than you'd dose in humans, and then seeing what doses are not toxic. this informs the first dose youd do in humans

the initial human studies are not done to study effectiveness, but to study safety. based on the data from your tox studies in animals, as well as other studies, you gradually dose cohorts of patients with higher doses, watching carefully for safety signals.

Re: Haemophilia A trial results 'mind-blowing'

#100

Post by aaavl2821 »

vanderZwan wrote: post #93
aaavl2821 wrote: post #41

Earlier quoted context omitted.

There are lots of people working on regenerative medicine and gene therapy for autoimmune diseases (ive worked with several researchers focused on type 1), but unfortunately the field isnt there yet. hemophilia a is a disease caused largely by deficiencies in one specific protein. massive technological breakthroughs in recent years have enabled scientists to deliver genes to human cells to consistently, accurately an…

From what I understand, autoimmune diseases are a mix of genetic predisposition and "learned behaviour" by the human immune system, i.e. some stressor making the immune system mislabeling a part of the own body as hostile. Once this is "learned", would removing the genetic predisposition even have an effect? Do we even know how the immune system "remembers" previous illnesses? If not, gene therapy can only be applied…

We actually have a pretty decent understanding regarding how the immune system remembers illnesses, although it is above my pay grade. if interested, read up on "adaptive immune system"

the genes involved in autoimmune disease are not as well understood as in some other diseases, and the individual contribution of any one gene is pretty small in autoimmune disease (compared to, say, spinal muscular atrophy). so as you say, a gene therapy approach might not be the right tool for the job.

a lot of current approaches focus on "retraining" immune cells to be "good" rather than "bad" cells. here's a blog post about one of the leading startups in the space which was acquired by celgene, a large biotech company, for almost $800M earlier this year, just 3 months after raising their series a: https://lifescivc.com/2016/09/re-balancing-immunity-via-regu...

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