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 and sustainably produce specific proteins. so treating diseases like hemophilia a has become tractable
however, autoimmune diseases are much more complex and there is no single protein or molecule that causes the diseases. in type 1, people have been trying to discover 1) the "triggering" event and 2) the autoantigens that cause the disease for years, and it looks like there is no "silver bullet". current drug technology can target only one, or sometimes two, disease-causing molecules, so for a disease where many molecules each play a small part, we dont have the answer yet
there are a few promising type 1 companies (semma, viacyte, others) trying to turn stem cells into insulin producing cells, but those cells are often rejected by the bodys immune system. some other companies are increasing the number of "regulatory T cells", basically T cells that inhibit autoimmunity (caladrius, celgene / delinia, parvus, lilly / nektar); these have shown promise but it isnt likely theyd be curative, as they just stop the autoimmune attack but cant regenerate beta cells that are already lost
if youre interested in type 1 research, diatribe is a great website that aggregates the latest science and presents it in a way that is easy for non-scientists, specifically patients and their families, to understand https://diatribe.org/
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].
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...
Thankfully artificial pancreas are looking like a good option until we can get to curing type 1. Not only does it save the number of shots like pumps we have today, but it can measure the sugar level and keep the swings down to a minimum. http://www.jdrf.org/research/artificial-pancreas/
They seem good as long as the patient's skin is not allergic to the adhesive used to attach it to the body. I know someone who had an insulin pump that worked perfectly except after a day or two, they would get a rash on the skin and the area would swell up blocking the delivery of insulin.
Nothing like all this great technology that could save your life that is foiled simply by the type of glue used by the manufacturer.
yeah artificial pancreas seems to be the most promising near-term development. the field has suffered from a lack of funding for translational research as VCs have been focused on other diseases, but hopefully that changes. semma (a startup turning stem cells into beta cells) raised $114M last week
Why are they focused on other diseases? Diabetes is hardly a rare disease, nor one with a low impact on its sufferers. So if what you say is true, what is it that's broken about the market for diabetes treatment?
I often hear it said that problems such as this are caused by cures being less profitable compared to drugs, because drugs are purchased repeatedly, cures only once. But competition is supposed to solve that problem. Is inappropriate regulation the real problem?
My kiddo has been dealing with Type 1 for two years now and I'm endlessly encouraged by developments in this area. She's just switched to a closed loop pump (Medtronic 670), which helps automate her insulin delivery through automated microdoses (think pump on a PID), but it's still a ridiculous pain in the ass. For example, she didn't notice her reservoir was low this morning before she left for school, now she's got an extra stressor in her life that wouldn't be there otherwise.
And despite all of the amazing technological and medical advances over the past 10-20 years, the best insulin therapy in the world is still comically shitty when compared to a healthy pancreas.
Anyway, it could be way worse and I'm grateful for what is available to us today. Still hope for better days ahead.
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 systems of these animals are very fickle and almost any environmental perturberance can change an immune response
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 them to live in comfort while contributing to humanity as experimental subjects.
I realize the mind recoils instinctively at these ideas, but it seems so frustrating and horrific that we have to delay life saving medical advanced due to insufficient experimental subjects.
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.
IIRC There's already a special case where you can volunteer to try things if you're dying. If you have a rare cancer and doctors are like "Six months maybe less" and there's some crazy Hail Mary drug, which could work but isn't tested yet, you can volunteer to try it and see what happens. You can't pay (so it's for science, not a chance to get rich selling false hope), and you must be advised by doctors who have no financial interest, something like that. Judges were like, eh, you're dead anyway, what's the worst that could happen?
This trial was phase I/IIa which I believe means it's combining safety in humans with initial efficacy data. The thinking is, the real treatment is a single dose. If we give participants less than a full size dose we don't learn much from that. If we give them a real dose, we might as well see if it works.
So their endpoints were firstly how is the treatment tolerated, then secondly does it reduce the need to take clotting factors? Hence this good news story.
Awesome outcome. But the article is yada-yadaing over the good stuff. How are the new genes integrated into the patient's body? Why isn't the virus attacked by the immune system? Instead of regular factor shots, do they need regular viral-gene shots?
"""After infusion, antibodies to AAV5 were detected in all the tested participants, but no T-cell–mediated immune responses to AAV5 capsid proteins were detected, and neutralizing antibodies to factor VIII did not develop in any participants. The absence of factor VIII inhibitors during more than 1 year of follow-up underscores the safety of AAV5-hFVIII-SQ. As has been observed in similar clinical trials of vector gene transfer,13,19,29 vector DNA was detected in various biologic fluids obtained from all the participants (see the Vector Shedding–Discussion section in the Supplementary Appendix). The possibility of vector integration was not assessed. The protocol was not designed to measure whether AAV5 infection was present in family members or close contacts, and ethics approval was not sought to pursue this question. The two viral genes within AAV5 have been replaced by factor VIII, and AAV5 requires another virus such as an adenovirus for a productive infection."""
This is a surprising finding because normally AAV5 leads to an immune response in this kind of treatment, although symptoms are mild and the virus in general is not considered pathogenic.
> I think if this worked as intended, no additional treatment is required.
It is correct if the therapy is targeting all stem cells. I have not understood clearly from the article but it seems the treatement is targeting "living cells". Once all your 'fixed' cells have been renewed you would need another round of treatement.
I have Haemophilia A, I was actually offered a place on an earlier trial although I didn't do it. It was explained to me that you would not need further gene treatments even though it targeted adult cells.
I think most cells are made by mitosis and don't come from stem cells.
Thanks for sharing! Can I ask what considerations went into your decision? Will you be pursuing this now that there is more evidence that it's effective?
I mean, obviously I regret it now, but at the time I had no idea it would work. I'm sure the next trial will be extremely oversubscribed! I think my trial was actually for a low dose version to test safety of the vector and it didn't have any clinical effects.
Its quite incredible though, there's only a few thousand people in the UK with haemophilia - this trial just cured like 0.5% of them
Would you mind keeping us updated if you pursue the next clinical trial? Happy to kick in Patreon money for your time. (Not a wierdo, just deeply interested in Curing All The Things).
well, stem cells are special in that they form tree replication structures to avoid problems like the Hayflick limit, so if the ones high up in the tree got repaired, you should have new stem cells born that inherit the fix for decades. At least, that's my understanding of the theory; that's no guarantee it works that way in reality.
What a fantastic gateway to show how gene therapy can completely resolve diseases. Many diseases are as simple as your eyes being brown vs blue - you simply have or lack particular proteins.
I couldn’t find it on a cursory reading, does anyone know what vector they used to achieve liver sinusoidal cell specificity? My understanding is that many gene therapy studies have used blood cells, which can be pulled out of the body prior to gene therapy, the advances in viral vectors may be just as empowering as the therapy itself. Imagine, in all the irony, getting “vaccines” as a child via viral vectors against common causes of poor health local to your birthplace. An enjoyable quote from a Paul Berg which holds true, of course - “Fears of creating new kinds of plagues or of altering human evolution or of irreversibly altering the environment were only some of the concerns that were rampant”.
Many diseases are as simple as your eyes being brown vs blue - you simply have or lack particular proteins.
I wish it were that simple. :(
Eye color, for example, is influenced by a combination of multiple genes. There’s no straightforward eye color gene.
Likewise, it’s especially true for diseases when something like “stomach cancer” is actually a dozen different diseases where each is influenced by dozens of different genes that share symptoms. Combinatorial explosion is a real problem.
The original comment was not suggesting that all genetic diseases and cancer (!) can be easily cured. Based on similar techniques, many single-gene disorders are effectively cured. Unfortunately, our disease-specific drug approval process does not scale and prevents us from realizing the benefits of these techniques and technologies.
As a personal example, a close family member was recently diagnosed with shwachman-diamond syndrome (SDS). I have confirmed with multiple leading physicians (Dana Farber, Mayo Clinic, etc) that all of the tools necessary to cure her are presently available. At a high level, this would involve:
1. Extracting marrow.
2. Isolating blood-cell producing stem cells & amplifying in a dish.
3. Modifying using a product like [A]
4. Validating/re-sequencing to confirm transduction.
5. Re-insert modified cells into patient.
Yet doctors can't engage in this work without going through the lengthy drug trial process. So instead, they recommend much riskier treatment options including some that would complicate future gene-therapy attempts.
> Based on similar techniques, many single-gene disorders are effectively cured.
This is a bit of a leap. In principle (some of) the technology "is there" but there is a huge amount of complexity in the steps 1 through 5!
> Yet doctors can't engage in this work without going through the lengthy drug trial process.
I think it needs to be said that the "lengthy drug trial process" exists for extremely good reasons. Were a treatment to be shown to be so incredibly effective during the trial process, based on pre-defined statistics monitored by an independent data safety monitoring committee, the trial would be stopped as it would be unethical not to provide all patients with the clear benefits. (recent example: https://www.ncbi.nlm.nih.gov/pubmed/29132880)
> So instead, they recommend much riskier treatment options including some that would complicate future gene-therapy attempts.
I believe it is unquestionable that doctors should be advocating treatment based on the best available evidence, and that the process for obtaining said evidence is a thorough and rigorous as possible, otherwise great harm can be done (classic example, thalidomide).
I would question the doctor that routinely recommended an experimental treatment which has not been shown to be efficacious
over a "risky procedure" which has been shown to have $X efficacy.
Making patients aware of trials which may be of benefit to them is a valid and valuable part of medical practice, which is not always done very well. This is improving (in the UK at least) with greater numbers of research nurses and the use of databases such as https://www.ukctg.nihr.ac.uk.
Excuse my ignorance here, but has there been a single other drug that the FDA has stopped before it became an issue that a less insanely thorough process wouldn't have? It seems like the FDA was right about thalidomide and has been using that as justification ever since. At this point, clinical trials have become so onerous that the FDA can't even vet them and just trusts the drug companies to be above board.
> Unfortunately, our disease-specific drug approval process does not scale and prevents us from realizing the benefits of these techniques and technologies.
On the other hand, something which is exceptionally well known to work should also attract huge and immediate capital to do the proper tests. Even for rare diseases, a sure thing would be funded.
I think the difficulty is more about procedural or cell based cures vs. drug-based cures or treatments. The system is set up for the latter, but is not comfortable with the former.
> Even for rare diseases, a sure thing would be funded.
Only if there is a ROI. Which also means that even treatments for not-so-rare diseases don't get funded if the majority of patients won't be able to afford the treatment at a price that provides that ROI. Clinical trials in the US or Europe are insanely expensive and you cannot even budget them: Adverse reactions by "male patients over 45, born on a new moon Tuesday"? In worst case you restart the trial, excluding the problematic group to at least get the proof of safety and effectiveness for some part of the population so you can finally make some money...
But for an insurance company, the ROI on curing someone’s hemophilia may be very very large.
On the more consumer side of things, being able to fix some sort of obnoxious but perfectly survivable condition that genetic engineering may be able to solve (say lactose intolerant) may be something that you could sell to a lot of people.
Surely an insurance company would prefer that the patient go elsewhere rather than have to pay $100,000+ every year on treatment. Even if they lose a customer, at least they don’t have that enormous expense.
Yes, but for any disease there are a number of known gene polymorphisms that predispose you to the disease. These genes may interact with the rest of your genome in incredibly complex ways, but I bet all it would take to cure a disease in most cases would be to target the one or two most prevalent polymorphisms.
"You bet"? This is one of the core questions in human genomics/health research today and nobody has been able to make a convincing argument in general that your proposed approach would work.
Would you agree: The question being specifically whether in most cases necessary-even-if-not-sufficient genetic traits can be found ("genetic traits", as opposed to "genetic illnesses" since illness may not be the most likely result.) The problem being that although so far most of our exciting findings are of at-least-necessary genes (or plural genes, etc); obviously it's just these sort of cases that will produce high correlations and grab attention, so there should be a presumption of the equivalent of "publication bias." Necessarily, these will be the low-hanging fruit even if such cases are actually the exception, overall.
Of course, mere and relatively small correlations between disease and genetic traits are extremely common; but there are lots of possible explanations of such findings. In some cases 16 percent of all genes have a small positive correlation to a given disease, and "if everybody is at fault nobody is at fault!"
unfortunately that usually isnt the case. there are very few diseases where one mutation or molecule is truly causative. in many areas, weve approached the limits of how much we can treat disease by just targeting one molecule or mutation. this is an area where $50-70B of pharma R&D spend goes each year for the last few decades, and the yield of that research in terms of approved drugs is declining exponentially
While it may sound easy to change a polymorphism (and even there only for a single base, don't get me started on larger structural variants), do not forget that you have to apply this one single change to 10 ^ 14 cells (or even just 1 in 10000 cells is 10 ^ 10), while evading the immune system and not inducing any detrimental other mutations. For a software developer it always sounds so simple just to fix a single spelling mistake but that really isn't it.
(+ obvoiusly the stuff from the other comments about how hard it is to determine the cause to begin with)
True, and it's probably also worth noting that even "single gene" diseases can still be environmental illnesses; dependent on a modern condition or conditions that didn't occur a hundred thousand years ago or more; and nonexistent (despite the presence of that gene) back then.
viruses are useful because they have evolved to insert foreign DNA into host cells. nothing humans can conceivably engineer has come close yet to the ability of viruses to do this
however viruses have also evolved a lot of bad qualities that cause disease. AAV is nice because 1) it is not known to cause disease, 2) only causes a mild immune response (so the body doesnt reject it before it does its work) and 3) is replication defective, so it wont reproduce uncontrollably in your body
all that said, viral vectors are far from perfect. the biggest issue is that you can usually only inject them once. after one injection, the immune system learns to recognize the virus as foreign, and upon subsequent administrations it will kill the virus before it can transfect cells. also, there is some risk that the viral genome can integrate with the host genome in ways that arent ideal.
from what i understand, the liver and the eye are really the only easily targeted specific tissues. the viruses are naturally carried to the liver, and the physiology of the eye enables viruses to get into cells there easily. getting viruses just to the brain, or heart, or pancreas, is much more challenging
aav technology has been around for a while, but there have been many false starts. back in the late 90s there were copmanies delivering genes into the brain with AAVs to treat parkinsons and alzheimers, and the genes got integrated and expressed by the right cells. however, the diseases were too complex for just one gene to cure them. in many ways, the advances in biology are enabling us to find what diseases are "right" for gene therapy, althoguh vector tech has improved as well
I sincerely think we are in the gene therapy renaissance. Delivery has always been an issue, but there are new tricks coming out with regard to cell-specific targeting. We can piggy back off the work done for RNA-based therapeutics (mRNA, ASOs, RNAi).
As for the CNS - Voyager therapeutics has had some great readouts in September in gene therapy for Parkinson's. More data coming out in Q1 to see second part of study.
i agree, the hemophilia data looks really good, and avexis' spinal muscular atrophy product looks great as well. i dont know much about voyager but just looked at their press release for the study; looks like they are delivering a gene to increase dopamine production? do you know if this could be a disease altering therapy or just a "better" levodopa?
its still pretty hard from what i can tell to deliver oligos to specific cells. delivery has been a huge challenge for ASOs, mRNA etc. viral vectors and autologous cell therapies have been used but have limitations, and antibody-tagged "targeted" nanoparticles have also been tried with varying degrees of success.
theres been some really clever developments in delivering oligos with cationic lipid nanoparticles to macrophages. biontech has an approach where theyve made nanoparticles that are naturally taken up by macropinocytosis by dendritic cells and macrophages. if you get the overall charge of the nanoparticle right (net negative i believe), the dendritic cells migrate to the spleen (rather than the lung with positive charge), where they can present antigen encoded with mRNA to t cells. they also have some interesting mRNA tech that increases the transfection efficiency, as it is hard to prevent oligos from getting degraded in lysosomes before they are translated. genentech paid them $310M upfront for a preclinical asset
Yes, you could frame the Voyager treatment as "better levodopa". Though, the mechanism would feasibly mitigate neuro-degeneration and improve the terrible dose escalation of the drug.
Also correct about general delivery difficulties. Hadn't heard of Biontech's method - almost sounds like voodoo by your description.
I think there is interesting blocking and tackling happening on an organ-by-organ basis. E.g. GalNAc for liver hepatocytes, LNPs for systemic mRNA therapies, direct injection for eye or CNS (cheating, but still works). I'm partial to exosome hype...
Also no such discussion is complete without saying CRISPR, but the point remains that you can conjugate it targetted vehicles like antibodies. Conjugating to antibodies seemed to work for Stem :p
I dont understand the biology behind biontechs spleen targeting secret sauce (i dont think they did either, but it got them a patent on an otherwise standard lipid formulation). there is a really good nature paper from summer 2016 that outlines a lot of their preclinical dev; the CEO said he sort of regrets publishing that as a lot of competitors sprang up afterwards
out of curiousity, what's the exosome hype? ive heard a few strong life sci VCs mention it, but i talked to a ceo of an exosome company and didnt quite understand the specific therapeutic potential
thats a good question, im sure theres a good answer but i dont know it
id imagine the immunosuppressive dose would have to be pretty strong and come with a host of other risks. i know the immunosuppression load for gvhd is pretty heavy, and corticosteroids are not fun drugs
Brown, green, hazel eye colors are variations in the amount on melanin in the iris. This amount can change as one gets older. Babies can have lighter eyes that become darker.
Blue eyes are believed to be caused by an isolated, inherited gene, OCA2. This gene is present in all people that have blue eyes. It disables the production of melanin in the iris.
All blue eyed people are believed to have a common ancestor from 6000 to 10,000 years ago, the first person with blue eyes (originally caused by a random mutation). It’s harmless enough that lots of us have it now.
huh. So where does the dominant/recessive traits we learn about in high school play into that?
I ask because my niece had blue eyes as a baby. This didn't make any sense because my sister was Indian, our parents were from India, their parents were from .. well I guess now it's Pakistan, but they migrated during the partition.
My sister married a white dude, but still it seemed very unlikely her daughter wouldn't have brown eyes. That's when we found out my grandmother got her education in Europe, and came back pregnant. Apparently divorces at the time were so shameful that it was better to tell your child their parent died.
My nieces eyes are now a bit hazel/blue-green ish. My grandmother passed away not too long after that, and that secret would have died with her, if it wasn't for the fact that my niece had blue eyes.
Not sure where your question comes from - one common ancestor could nonetheless have had a recessive trait (though selection for it might not kick in until it was visible.) It's not directly relevant, but I might mention there are many sorts of genetic combos/phenotype patterns, not just plain recessive and dominant.
It's likely not harmless but very positive to spread so quickly. I think one hypothesis is the domestication of dogs. They don't usually track fingers, but they do track eyes and having blue eyes may help there. There are many types of melanin - I believe the gene only cuts out one kind.
>Many diseases are as simple as your eyes being brown vs blue - you simply have or lack particular proteins.
I think the other half of this is the microbiome. I have been speaking to physicians about leaky gut recently and a great analogy is the protein genes are like a piano and the microbiome is like the musician.
As you suggest the genes/piano is sort of the hand you are dealt (you have the gene for certain disease or not), but the microbiome is what will typically unlock those diseases or not given the gene set. Another way of explaining this is that humans have about 20,000 genes, the most genes in any animal are about 35,000, and wheat has 164,000-334,000 genes. Obviously we are much more complex with the potential to carry many more diseases which physicians explained to m through humans having a microbiome.
> 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 factors (i.e. not the same as a protein dictating whether you have brown or blue eyes)? To my point re the microbiome google points to multiple studies including but not limited to:
> Here are just some of the health conditions that involve our microbes:
Acne
Antibiotic-associated diarrhea
Asthma/allergies
Autism
Autoimmune diseases
Cancer
Dental cavities
Depression and anxiety
Diabetes
Eczema
Gastric ulcers
Hardening of the arteries
Inflammatory bowel diseases
Malnutrition
Obesity
>Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome.
>Researchers have discovered that a powerful guardian gene known to protect against a variety of autoimmune diseases, including type 1 diabetes, is triggered by the bacteria in our gut.
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.
"microbiome" therapies has been one of the hottest areas in biotech the last five or so years. some of the hype has died down, however. microbiome therapies work well in c. difficile infections and some other gut diseases. in this case, you give a patient a set of "good" microbes that fight the "bad" microbes (c. diff).
people are studying microbiome therapies for cancer, autoimmune disease, cns disease, etc, but its way too early to tell if any of it is real. there are many challenges: how do you ensure the microbes you administer stay in the body, colonize, and actually produce the molecules you want them to? how do you manage the risk that they interact with other microbe populations in ways that are impossible to predict accurately, but potentially very harmful? how do you manufacture these things in a consistent, high quality way? what is the regulatory path? how do you justify a huge risky r&d investment when you can't patent a microbe? not to mention the biology risk; the "microbiome thesis" sounds nice, but how confident are we that microbes can treat cancer, depression, parkinsons? right now, not very
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" bias, like "Your 13+ years of steady forward health progress in the face of your degenerative condition is merely wild coincidence and doesn't prove that you know anything at all. Stranger things have happened!"
Cuz, yeah.
People who see themselves as scientific and logical are very often not remotely objective. They just have college degrees or whatever to justify their ugly personal prejudices, and don't confuse them with the facts.
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.
The gut contains 70% of immune cells because your gut is actually the main point of contact between your body and the external environment. The surface area of your gut is somewhere from 20x to 100x that of your skin.
One could just as well argue that because the immune system is so well developed and robust in the gut that it's the last place to look for dysfunction. Or one could argue that a 70% share of immune cells is rather low considering the relative ratio of environmentally-exposed surface area.
We could say all kinds of things if we're free to make unsubstantiated conjectures. But we really can't say anything of substance without context and evidence. The human organism is ridiculously complex and consistently defies intuition.
If you've "heard it", but you can't recall where, you should absolutely not believe your own claims. Either find the source again, or concede that you might have made it up. Because you are the easiest person to yourself to deceive into thinking something that isn't true.
As you suggest the genes/piano is sort of the hand you are dealt (you have the gene for certain disease or not), but the microbiome is what will typically unlock those diseases or not given the gene set.
The way I used to describe it was that your genes are like the blueprints for a house and what you eat is like local building materials. The blueprints may specify 2 bedrooms, one bathroom, but exactly how that will look will depend a lot on the vernacular architecture. Is it adobe brick because you live in the American Southwest? Is it made of blocks of ice because you are an Inuit? Etc.
So, different building materials have different strengths and weaknesses. This will significantly impact things like ceiling height and room size because what shapes the material supports will vary, depending on the material.
I'm sorry some people are reflexively downvoting. I hate it that so many people who imagine themselves to be scientific are so incredibly dismissive of stuff like this.
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 ensures that dose control is effective, if the virus could replicate then further copies of the gene would be inserted.
One of the reasons haemophilia appears to be more treatable by gene therapy (than other diseases) is because the cells that should be producing the clotting factors are found in the liver. When virus carrying the gene therapy enters the blood it is collected by the liver's filtration mechanisms, conveniently aggregating the gene therapy in the tissue that the gene therapy is targeting.
It is hard to target gene therapy toward specific cells/tissues but the liver makes targeting haemophilia with gene therapy easier.
This is awesome. I have Crohn's and am looking forward to an eventual cure.
One thing I don't understand is why big pharma and VCs seem to focus on rare diseases instead of a gene therapy for changing eye color or hair color. With eye/hair color gene treatments, patients could undergo the therapy multiple times (if desired) and the pool of patients is all humans (not just rare diseases sufferers). This allows for amortization of the R&D expense over substantially more treatments. Plus the advances in gene therapy technology could then be applied to therapies for rare diseases
the cost of manufacturing a gene therapy would probably exceed what most people are willing to pay for changing eye or hair color. why use gene therapy when colored contacts or hair dye work, and much more easily reversible in case you dont like it?
also, it is incredibly expensive to get a gene therapy through fda trials. there hasnt really been a "true" gene therapy approved in the us yet (excepting car-t), and the first two approved in europe were pulled from the market because they werent profitable even at a price of $1M per patient. thats why these companies go after severe rare disease -- you can charge more for saving a kids life than you could for changing hair color, and you have to charge a lot to justify the expense and incredibly high risk of developing a gene therapy. and with a rare disease, you can go to market with a 20-30 person sales force to cover all patients, whereas to market a hair or eye color thearpy youd need thousands of people calling on every hair salon and eye doctor in the country. as of now, the success rate in terms of fda approval for gene therapy is 0% -- thats an important input in financial calculations.
further complicating things is that you generally cant dose these drugs more than once bc your immune system rejects the vector after the first dose, so you have to get all your economics upfront
These may be outweighed by the potential market size of 3 billion people (a rough estimate of everyone connected to the internet). If R&D and manufacturing have a total cost of 10 billion dollars, then this reduces to $3.33 per person of the potential market size.
>cant dose these drugs more than once
This may be a showstopper for now. At a certain point, the technology should improve to allow multiple treatments so that a single individual could have red hair for a year, blonde hair for a year, black hair for a year, ...
The cool thing about growing blonde hair instead of dying hair blonde, is that nothing more needs to be done and no further treatments need to be had (unlike dyes). This does assume that the individual has enough patience for the growth process
I am sorry for that but to be honest your comment suggests that you do not have tiniest idea of how hard medical research is. Not only are the topics you suggest much more complicated than rare diseases (i.e. we do not know the exact molecular process but they are certainly much more complex and in the case of eye color, entirely developmental, so changing the genetic background would not switch your eye color), but also much more expensive (for these are nonmedical applications and therefore side affects would kill your drug). So we are talking in the order of 10 billion in R&D expenses. And then, unlike in case of orphan diseases, your patents will be weak and the margin will be low (compared to cost).
I am sorry, but to be honest your comment suggests that you do not have tiniest idea of how insulting the first sentence of your comment is. Instead of simply conveying the idea that things are expensive, the first sentence of your comment is styled as a personal attack, which does not add to the discussion and should not have been included. For example, an alternative first sentence, which conveys the point being made without being a personal attack would be "Medical research is hard."
Regarding the substance of your remarks, if 10,000 people have a rare disease then the 100 million dollars it takes to develop that therapy can only be amortized over that small pool, which translates to $10,000 per person, assuming that every person pays for the therapy.
If 3 billion people (a rough estimate of everyone connected to the internet) is the market size for hair/eye color treatment and the 10 billion dollars of R&D gets amortized over that full-size, then the cost is $3.33 per person. If only 10% of people want to change colors, and only 10% of those people are willing to partake in the therapy, then the cost becomes $333.33 per person to amortize the R&D expense, which is in the same order of magnitude as contacts or a salon hair treatment.
I can think of a couple of reasons. First, they think of themselves as companies that address diseases. They are concerned with the ill, rather than people seeking cosmetic changes.
Second, I can see some potential for major backlash. Literally going into the business of designer babies? Ethically tricky. Doing it only for the rich, because it'll be incredibly expensive at first? "Tricky" doesn't begin to cover it. Public policy in first-world countries is not always noted for being far-sighted and even-handed, and a public backlash could easily shut down all gene therapies.
>they think of themselves as companies that address diseases. They are concerned with the ill, rather than people seeking cosmetic changes
Agreed. The joke being that black hair (or blonde hair or red hair) is a disease that can be "cured" by a different hair color :)
>backlash ... [against] designer babies
Agreed that this is an issue, especially if the treatment were marketed at unborn children. It may be better to focus on cosmetic treatments for adults to try and avoid this.
I expect this technology will eventually become ubiquitous in our lifetimes, with the only question being the time frame for which it will come to pass
>Historically, MAP in humans has been difficult to study as it cannot be seen under an ordinary microscope and is very difficult to grow. Testing for MAP by the presence of its DNA (using PCR) has found MAP in up to 92% of Crohn’s patients but until now no-one has developed a test to show MAP in-situ in the tissues of people with Crohn’s disease.
It is fascinating that there is a virus that evades regular diagnostic techniques (i.e., using a microscope). That the virus can be found using genetic testing speaks to the power of genetic technology and how revolutionary the true understanding of genetics will be
>cosmetic changes that can be easily done by less expensive means
The less expensive means (contacts, hair dyes) are temporary and require maintenance. The benefits of a genetic treatment is that it is permanent (no cleaning of contacts, no subsequent salon visits), but should also be reversible
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 led to a greater string of consequences? Malaria, Spanish Influenza, polio, AIDS?
Some high-end estimates of the Spanish Flu death toll are that it killed around 300 million people, which dwarfs the death toll of WW1 (49 million) and WW2 (73 million) combined.
We'd likely live in a very different world had it been prevented or curtailed, though it's hard to know what specifically would be different, as even the existence or non-existence of a single person could be pivotal in history.
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.
Possible, but... Russia being able to mobilize faster at the start of WWI than the Germans believed possible diverted enough additional troops East (busting their original plan) that the German invasion of France was too weak to succeed. There may be a better argument for Russia being stronger than could reasonably have been expected. Granted, French-subsidized railways and Austrian incompetence were very large factors, here.
The follow-on Kerensky government proved even less effective militarily, although it can be argued that the consequences of a century of mismanagement favoring the 1% wasn't easily reversed.
Malaria has defeated many an army and invasion; yellow fever, too. The fall of Rome has been blamed on a severe plague; particularly the fact that Rome was hit last, and therefore weak when it's neighbors were recovering and stronger.
Interesting question. Can the eradication/treatment of a disease be taken into account? Would think the wide-scale availability of vaccines for Polio/Small Pox/other various viruses etc coupled with antibiotic treatments for bacterial infections had an enormous impact on the last 100 years.
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.
Some figures: I got my "every second month" injection of Eylea this morning, https://www.macular.org/eylea-injection-treatment. It cost $800 Australian dollars. Under our health scheme, I get $600 back. The guy beside me in the waiting room has been having injections for 17 & 1/2 years, that is, since the year 2000. He gets state-assistance to fly down 800 km to our capital city from the country. The lady across the aisle from me in the packed waiting room, has a relative drive her down from a regional town every second week, as she has macular degeneration in both eyes, with the alternate eye being treated on alternate visits. I give you these cases to illustrate that a lot of money is being presently spent on treating this disease. I have heard the incidence of macular degeneration in Australia described as an epidemic. Obviously, everyone would like a cheaper, longer-lasting treatment. That's what I am hoping the modified-virus treatment provides.
The figure that jumps out of the page for me in the modified-virus report, http://www.aips.net.au/news-events/the-florey-medal/2017-pro..., is "This therapy has been licensed to US company Avalanche Biotechnologies Inc., which has raised over $400 million to progress the treatment through clinical trials and bring it to market." This figure of US$400 million takes my breath away. I note one of Prof. Rakoczy's clinical trials in Australia on 32 patients was done with a AU$370 thousand grant, among others, https://demo.ands.org.au/long-term-follow-gene-therapy/10789.... I guess the US$400 million trial will be more extensive. This means a few more years will have to go by before this comes to market (if it indeed does).
I have found an open source article about Prof. Rakoczy's trial, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161436/. I note they removed the vitreous humor to place the modified-virus under the retina (termed a vitrectomy), recording that "It is not yet clear if subretinal injection can be done safely without vitrectomy". They seem very pleased with the results of that phase 2 trial.
This could be huge. Hemophilia is one of the most expensive diseases to treat out there. I worked with a client that provides software to hemophilia clinics, and while modern factor drugs have made it so that sufferers can live relatively normal lives, it's still a very challenging disease with many long term complications.
This is so exciting. I feel like we're really at the cusp of a complete change in our expectations of how we treat disease, what cures look like, what they cost, and the range of improvements that can be made to people's lives.
Yeah I apologize, I should've linked to a more informative article.
From another news release:
Investigational SPK-8011, a novel bio-engineered adeno-associated viral (AAV) vector utilizing the AAV-LK03 capsid, also referred to as Spark200, containing a codon-optimized human factor VIII gene under the control of a liver-specific promoter, is being studied as a potential one-time gene therapy for hemophilia A. It is the second investigational hemophilia gene therapy to emerge from Spark Therapeutics’ leading gene therapy platform. Spark Therapeutics retains global commercialization rights to SPK-8011.
We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX–R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values.
I hope they can expand this to other genetic problems. There are hundreds of genetic issues science knows about. Just off the top of my head I can think of high cholesterol, cystic fibrous, and sickle cell anemia. I know there are others, but I'm just a layman not a medical doctor. Those who have any of the above would like to be cured.
The trick right now is in knowing exactly what gene to express. It's like the Ionis Huntington's trial, just one well-known gene to suppress (albeit in cerebrospinal fluid, so the stage 1 trials were interesting). And of course, the first-wave funding will go to stuff that absolutely, positively will kill a person stone dead.
As soon as there's multiple targets it gets more complicated. Familial Hypercholesteroleamia could be any of three genes in it's least complex setup. I wouldn't be surprised to see a scam "therapy" marketed for it by the end of the year...
Yes, there is a company whose name escapes me working on it - Bluebird? You insert the correct hemoglobin gene and express it at a high enough level that you drive the percentage of sickle hemoglobin low enough that you no longer get the sickle cell crises.
Last I read they were having trouble getting durable expression.
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.
So we can engineer a virus that inserts arbitrary DNA into our cells? What are the limitations of that? Sounds like the approach could be used for a lot other useful things.
