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HIV in cell culture can be completely eliminated using CRISPR-Cas gene editing [pdf]
- eganist 3y agoWay out of my depth here, but I'm guessing the main hurdles to turning this into a drug are encapsulation in a way that survives injection (or better yet, ingestion) as well as either targeting of infected cells or at least ensuring that even if it touches every cell, it only affects HIV DNA? Basically, what's needed to commercialize this?
- colechristensen 3y agocrispr also makes mistakes. The kind that lead to cancer, disability and death. It’s not a magic wand. Being able to do something in cell culture is interesting but very far away from a therapy.
- smt88 3y agoHow do Casgevy and Lyfgenia[1] avoid these dangerous mistakes? Is it something that can be generalized to other therapies, or does it need to be recreated for each "edit" that we want to turn into a therapy? 1. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease https://www.fda.gov/news-events/press-announcements/fda-appr...
- ghkbrew 3y agoAccording to your link, both of those are applied to extracted stem cells which are then reintroduced. The ability to perform clonal expansion and DNA sequencing makes it possible that screening for off-target edits could be performed. Though I have no idea if it's actually done.
- jryb 3y agoYour point is broadly correct (not sure about disability though), but I think it overstates the danger of what will happen in practice. Yes, if you picked a random target and blasted away, you probably wouldn't have a good time. But anything that even approaches clinical trials is going to get substantial engineering put into it to minimize (and characterize) all of the off-target loci. If there's meaningful editing near an oncogene then that's going to be a deal breaker for a particular guide. When the FDA was discussing the Casgevy application, they went into remarkable detail of how Vertex had measured the off-targets - the regulators really, really don't want to approve anything risky. Frankly just getting it to work at all is the real hurdle in this case.
- _heimdall 3y ago> If there's meaningful editing near an oncogene then that's going to be a deal breaker for a particular guide. At this point do we know every gene that had the potential to cause cancer?
- a_bonobo 3y agoWe roughly know the space of possible mutations in the human genomes because we have so many sequenced genomes now: if we don't spot a mutation it's probably not good when it happens, survivorship bias. The problem with CRISPR is that we cannot control where the off-target effects happen, we can currently only optimise the guiding RNA and the Cas enzyme to have as little off-target effects as possible (but not 0, yet). It would be cool to engineer guiding RNAs that bind in those high mutation-rate areas when they have off-target effects, stuff can mutate there and nothing will happen (probably).
- colechristensen 3y ago> Frankly just getting it to work at all is the real hurdle in this case This being the point. Many diseases have been cured dozens of times over in a tissue sample in a lab that never make it to actual therapies because the hurdle is elsewhere. The risks with crispr are as stated, especially flooding your entire body with it to target a virus.
- 3y ago
- aaauaucuggaa 3y agoGenerally speaking: - Delivery: getting the mRNA and guide RNA into the target cells - Expression: ensuring the target cell expresses the mRNA, thus making the protein - On Target Editing Efficiency: ensuring the intended edit happens at a high rate - Off Target Editing: ensuring other edits in other locations do not occur
- interestinghiv 3y ago[flagged]
- Brian_K_White 3y agoThe covid vaccines weren't crispr. Keep trying soldier.
- Terr_ 3y ago"Good soldiers follow orde^H^H^H^H talking-points." (To wit, I bet someone heard "the vaccine rewrites your DNA" bullshit again somewhere, so it must be true...) https://hcrl.wustl.edu/claims-that-mrna-vaccines-change-human-dna-are-back/ https://hcrl.wustl.edu/claims-that-mrna-vaccines-change-huma...
- tjpnz 3y agoAnd that Bill Gates wants to use the vaccine to depopulate Earth, and that the vaccine includes a 5G enabled microchip to coerce you into adopting SDGs. It's really bullshit all the way down.
- agnokapathetic 3y agomRNA vaccines are about getting mRNA into just a few non-specific cells which then instructs the cell to produce Corona Virus Spike Protein. This gets identified by the immune system which then makes antibodies targeting the spike protein. So the mRNA only needs to get taken up by a few cells to produce an immune response. The HIV CRISPR-Cas technique needs to target several orders of magnitude more cells in the body, and is performing a far more complicated procedure than simple transcription like with an mRNA vaccine.
- nextaccountic 3y agoDoes this means that in order to productionize this into a drug, one would need to basically engineer a biological virus?
- jjtheblunt 3y agohttps://en.wikipedia.org/wiki/Viral_vector https://en.wikipedia.org/wiki/Viral_vector
- lucioperca 3y agoor mRNA
- XorNot 3y agoCRISPR is pretty complicated - I'd say it's not clear whether mRNA of such length could stably produce enough enzyme in enough places. It's great when you need an antigen to be presented, but not so much when you need an entire restriction enzyme system.
- WheelsAtLarge 3y agoThere's a sickle cell therapy that uses CRISPR. I don't know the specifics but if one has been successful then a second can be too. I'm looking forward to getting more information in the future. Cell culture vs cure is a long road but at least there's hope. The big drawback is that these therapies are super expensive but time and experience in the past have proven that the costs can be lowered. "Sickle Cell Disease Approvals Include First CRISPR Gene Editing Therapy" https://jamanetwork.com/journals/jama/article-abstract/2813761#:~:text=Casgevy%E2%80%94the%20CRISPR%2DCas9%20gene,preventing%20painful%20vaso%2Docclusive%20crises https://jamanetwork.com/journals/jama/article-abstract/28137....
- crakenzak 3y agoYup Casgevy & Lyfgenia! These sickle cell (and now also approved for beta thalassemia) CRISPR therapies basically work in the following way: - Blood stem cells are removed from the patient and the CRISPR Cas9 protein outside of the body is injected to cut the gene responsible for suppressing fetal hemoglobin production (even people with sickle cell have healthy fetal hemoglobin, their adult hemoglobin gene is what causes the deformed red blood cells) - Chemotherapy is used to kill all living bone marrow and remove all previous unedited stem cells. - New edited stem cells are inserted, and patient recovers with new blood production being of healthy red blood cells. I'd say a huge step forward was FDA and EMA approval, but figuring out a way to remove previous unedited stem cells with chemotherapy would be a step change in the patient experience.
- Etheryte 3y agoIt's both extremely sci-fi and incredibly terrifying that one of the steps for a cure is to quote unquote kill all living bone marrow. Modern medicine is fascinating in how advanced it can be.
- l33tman 3y agoYeah it's a spectacular transplant procedure, though it's really not that modern medicine, it has been developed since the 50s! The step where you irradiate or apply chemo to kill off the existing bone marrow had to be done at first because the patients had leukemia so you had to do this anyway. An interesting thing is that if there are still cells left in you, they will be wiped clean by the new transplanted immune system in a so called graft-vs-host response that also sounds like a horror-movie concept :)
- RcouF1uZ4gsC 3y ago[flagged]
- pazimzadeh 3y agothere's a million valid critiques of the news and this is the dumbest laziest one. people who comment "in mice" on all articles are more useful than your comment. for example: CRISPR is derived from bacteria so there is always the risk that the immune system targets the therapy Cas9 immunity creates challenges for CRISPR gene editing therapies https://www.nature.com/articles/s41467-018-05843-9 https://www.nature.com/articles/s41467-018-05843-9
- Retric 3y agoYou completely misunderstood the point being made by that comic. CRISPR unlike fire, a gun, bleach etc isn’t extremely harmful to human cells, we’ve used it to edit people’s DNA before. Ex: https://www.science.org/content/article/crispr-helps-blind-woman-see-doesn-t-help-all-patients https://www.science.org/content/article/crispr-helps-blind-w... So objecting because it needs to be injected into a human isn’t a relevant critique here.
- Brian_K_White 3y agoFire or chlorine are far less dangerous than crispr. Fire or chlorine are immediate and obvious. They can kill a person, but they can't modify one's behavior, identity (biometrics), or progeny, and all without either the victim or anyone else having any way to find out who did it or when, or even neccessarily detecting that anything was ever done at all. Crispr is infinitely more dangerous than any gun. It's equally powerful for good, but that just makes it worth it, it doesn't make the danger from unintended harm or intended harm go away, and the risk itself is a harm. I am absolutely in favor of using crispr to fight hiv, or any other good purpose it can be used for. But that comic was not necessarily inapplicable. As implied, what happens in a petri dish really doesn't mean much. It also was not necessarily pointful because although it's true the petri dish doesn't really prove much, it's also true that you have to go through a petri dish stage before you can get to the actually useful human stage, and so there is nothing wrong with celebrating the potential stepping stone or milestone and nothing gained by shitting on it.
- notfish 3y agoRelevant xkcd http://xkcd.com/1217 http://xkcd.com/1217
- ngcc_hk 3y agoIs it the greatest day or the worst day (or both at the same time) of humanity when CRISPR is invented ?
- wigster 3y agoprobably great for humanity 2.0 amazing and scary stuff
- passwordoops 3y agoLike nuclear
- epgui 3y agoProbably not "the greatest day", but definitely a very very good day. I think it's too easy to imagine Orwellian scenarios, but I think the real worries are much more subtle than people usually think, and they usually have more to do with how the world already works than with how it could change.
- kjkjadksj 3y agoWe had the ability to do what crispr did already, it just simplified the lab work. See TALEN and zinc finger nucleases.
- Khelavaster 3y agoYou'd hope so.. the treatment is already in phase 1/2 combined human trials! https://crisprmedicinenews.com/news/clinical-trial-update-positive-clinical-data-for-first-ever-crispr-therapy-for-hiv/ https://crisprmedicinenews.com/news/clinical-trial-update-po...
- Metacelsus 3y agoThe big problem is that the CRISPR would need to be delivered to 100% of infected cells. And as far as I know (I'm a biologist) nobody has a method that can achieve a delivery rate of 100% in vivo.
- cft 3y agoThat would be for a cure, but not for a recurrent therapy
- mlrtime 3y agoDo we even need a cure or therapy if we can essentially use this as a vaccine? Doesn't help people now, but may eliminate it as a threat for future generations.
- huytersd 3y agoWell you can’t use it as a vaccine since there would be no hiv to preemptively excise.
- 1letterunixname 3y agoWhat we need is a reliable CRISPR vaccine that confers the CCR5 SNP and essentially give it to everyone.
- huytersd 3y agoYeah, we don’t even need to get every cell at that point, just a sizable number of the CD4 cells that are relatively easily accessible. The HIV would destroy every CD4 that isn’t CCR5 by itself. The antibodies would clean up the rest of the virons. Theoretically that would work as a cure too if you could excise the hiv and insert the CCR5 widely enough.
- ac2u 3y agoCould that risk evolutionary pressure on whatever is left behind so that mutations emerge that are more aggressive?
- croemer 3y agoScience by press release. The results aren't even preprinted yet. Only some methods in a 2022 preprint. Looks hyped up, I'd ignore. > This press release is based on abstracts P0004 P0006, P0013, P0026 and P0004 at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). The material has been peer reviewed by the congress selection committee. Only material from P0004 has been published in a preprint article. The other three have not yet been submitted to a medical journal or as preprints.
- slackfan 3y agoYou can also eliminate most climate-change-causing pollution (and microplastics) via nuclear weapons.
- ta988 3y agohttps://xkcd.com/1217/ https://xkcd.com/1217/
- tslf 3y agohttps://open.substack.com/pub/timself/p/3-million-or-your-life?r=b4mje&utm_medium=ios https://open.substack.com/pub/timself/p/3-million-or-your-li... This might be of interest