13 ms·
Haemophilia A trial results 'mind-blowing'
- testfoobar 9y agoAwesome 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?
- deleted 9y ago[deleted]
- dekhn 9y agoThe virus is recognized, but not attacked: """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 The two viral genes within AAV5 have been replaced by factor VIII, and AAV5 requires another virus such as an adenovirus for a productive infection."""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. The mechanism of integration is described in detail in the wikipedia page. https://en.wikipedia.org/wiki/Adeno-associated_virus https://en.wikipedia.org/wiki/Adeno-associated_virus I think if this worked as intended, no additional treatment is required.
- seren 9y ago> 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.
- Chriky 9y agoI 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. Here's a screenshot of the explanation I received when I was invited on the trial -https://i.imgur.com/H329Vgv.jpg https://i.imgur.com/H329Vgv.jpg > "By using BMN 270 to provide the functional genes, it is expected that you may not require treatment for Haemophilia A, as often or at all." I don't really want to upload the whole Participant Information Sheet because it contains some of the doctor's personal details.
- seren 9y agoThanks for clarifying my misconceptions !
- jessriedel 9y agoThanks 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?
- Chriky 9y agoI 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
- 1_800_UNICORN 9y agoThis 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.
- alextheparrot 9y agoWhat 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”.
- carbocation 9y agoJournal article is at http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article They used AAV (actually, take a look at the article, they give a nice and clear explanation of what modifications they had to make).
- will_brown 9y ago>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.
- carbocation 9y ago> 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?
- sswaner 9y agoThere 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?
- mirimir 9y agoThe plague in Europe. And in North America, smallpox, which decimated (and more) indigenous peoples.
- TylerE 9y agoNeither of which occurred in the last 100 years.
- mistermann 9y agoI couldn't resist. https://twitter.com/codinghorror/status/895774914820546560 https://twitter.com/codinghorror/status/895774914820546560
- mirimir 9y agoOK, fair enough. Let's see ... 100 years. How about nationalism?
- mirimir 9y agoRacism, then?
- seren 9y agoJust to be extra pedantic, and not in a serious way, the 1917 Russian October Revolution, was neither in the last 100 years since we are in December.
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- bluGill 9y agoI 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.
- andygates 9y agoThe 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...
- pishpash 9y agoSo what was the actual therapy? That kind of title reminds me of BuzzFeed.
- colmvp 9y agoYeah 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. You read the paper from the New England Journal of Medicine here: http://www.nejm.org/doi/full/10.1056/NEJMoa1708538 http://www.nejm.org/doi/full/10.1056/NEJMoa1708538
- test6554 9y agoThis 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.
- wbl 9y agoThe issue in Type 1 Diabetes is autoimmune destruction of the islets of Langerhans, so the therapy would need to target the immune system.
- aaavl2821 9y agoThere 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/ https://diatribe.org/
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- toblender 9y agoScience bitches.
- toblender 9y agoScience, it works bitches.
- dang 9y agoPlease don't post unsubstantive comments here, and especially not snarky tropes.
- pdm55 9y agoAnother use of a modified virus is to deliver an antibody to VEGF, the factor that causes macular degeneration (blindness). Prof. Elizabeth Rakoczy has been recently awarded the 2017 CSL Florey medal for this work. http://www.aips.net.au/news-events/the-florey-medal/2017-professor-elizabeth-rakoczy/ http://www.aips.net.au/news-events/the-florey-medal/2017-pro... The video has a cartoon showing the modified virus being inserted in the retina. I think 40 patients have been successfully treated in a initial 3 year clinical trial. I found these links to abstracts of her recent publications, https://www.socrates.uwa.edu.au/Staff/StaffProfile.aspx?Person=PiroskaRakoczy https://www.socrates.uwa.edu.au/Staff/StaffProfile.aspx?Pers..., but I cannot find an open source research document. Some of her team members: http://www.scienceinpublic.com.au/floreymedal/2017-csl-florey-medal-photos http://www.scienceinpublic.com.au/floreymedal/2017-csl-flore...
- pdm55 9y agoSome figures: I got my "every second month" injection of Eylea this morning, https://www.macular.org/eylea-injection-treatment 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-professor-elizabeth-rakoczy/ 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/107896?source=undefined 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/ 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.
- tabs_masterrace 9y agoSo 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.
- Jemaclus 9y agoMy wife works on this project! This is so cool to see real-life stories of this. Awesome.
- johngaizick 9y agoHhv
- johngaizick 9y agoDsd
- mrfusion 9y agoCould we do the same thing with sickle cell?
- Nomentatus 9y agoSince 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.
- refurb 9y agoYes, 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.
- king07828 9y agoThis 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
- Kalium 9y agoI 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.
- king07828 9y ago>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
- pishpash 9y agoHow much can you charge for cosmetic changes that can be easily done by less expensive means? I'm sure they've done the math.
- hughes 9y agoThis 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.
- torbjorn 9y agoOne 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.
- tuxguy 9y agoThe NEJM paper : http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article http://www.nejm.org/doi/full/10.1056/NEJMoa1708483#t=article pdf: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708483 http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708483