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CRISPR eliminates HIV-1 infection in live animals

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Re: CRISPR eliminates HIV-1 infection in live animals

#51

Post by jonmc12 »

Animats wrote: post #32

Back in 2011, there was an announcement from MIT about a new approach to a broad-spectrum antiviral that appeared to work.[1] This goes way beyond an AIDS-specific cure. But it was at MIT Lincoln Labs, which doesn't usually do bio. So the researcher moved to Draper Labs, but didn't get much funding. Then that funding ran out. Now the guy behind this is trying to get funding on Indiegogo.[3] The problem seems to be th…

Might point him towards Propel(x) (https://www.propelx.com/). Its a newer syndicate model marketplace that focuses on "deep tech" investment. The team is knowledgable / motivated, and working to attract angels and institutional investors who understand these type of investments.

Re: CRISPR eliminates HIV-1 infection in live animals

#52

Post by roywiggins »

natch wrote: post #14

"animal models" is obviously a term of art but what does it mean in plain English?

Broadly, it's using an animal that is sufficiently like a human that it probably behaves similarly in whatever way is important for the study.

In practice they also often inbreed them to make them as identical as possible, and sometimes to induce specific changes. Ex: breeding mice that all get lung cancer would be an animal model of (human) lung cancer.

There are also transgenic models, where you might insert a human gene into a mouse to create a model of human disease, ex: inserting a huntingtin gene variant to induce Huntington's in mice and create a mouse model of Huntington's.

Re: CRISPR eliminates HIV-1 infection in live animals

#53

Post by dmix »

Animats wrote: post #32

Back in 2011, there was an announcement from MIT about a new approach to a broad-spectrum antiviral that appeared to work.[1] This goes way beyond an AIDS-specific cure. But it was at MIT Lincoln Labs, which doesn't usually do bio. So the researcher moved to Draper Labs, but didn't get much funding. Then that funding ran out. Now the guy behind this is trying to get funding on Indiegogo.[3] The problem seems to be th…

This is the type of innovation we exchange for a sense of absolute security in having highly-vetted decade-long bio R&D and extensive backlogs at the FDA for approvals to sell products on the market. It's go big or go home because the regulatory risk/timeline is so extensive.

Most of these things die quietly or never get started so we never really see the true costs of what it takes to push the pharma world forward. It likely has a big effect on reinforcing existing monopolies as they are the only ones who can play that game (and pharma has been dominated by the same six companies since the 1800s). Usually R&D happens via a single trajectory which is either expensive internal labs at these companies or via anointed universities. There is very little variation on the source.

There's rarely an investment market between small scale seed stage and high growth phase. Which is where these bio R&D projects die.

Maybe there is an opportunity for a YC-style org to disrupt here. But I doubt it given the requirements to get to market.

Re: CRISPR eliminates HIV-1 infection in live animals

#54

Post by degenerate »

rosalinekarr wrote: post #23

For anyone unfamiliar with CRISPR, I strongly recommend this quick introduction video from Kurzgesagt on YouTube: https://www.youtube.com/watch?v=jAhjPd4uNFY

This video is how I originally heard of CRISPR, and it's still the best video I have seen on the subject.

Re: CRISPR eliminates HIV-1 infection in live animals

#55

Post by brut »

From the abstract:

    Intravenously injected quadruplex sgRNAs/saCas9 AAV-DJ/8
    excised HIV-1 proviral DNA and significantly reduced
    viral RNA expression in several organs/tissues of Tg26
    mice. In EcoHIV acutely infected mice, intravenously
    injected quadruplex sgRNAs/saCas9 AAV-DJ/8 reduced
    systemic EcoHIV infection, as determined by live
    bioluminescence imaging.
Can a mod change the title to reflect the findings? The original title is "In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex Single-Guide RNAs in Animal Models" and should be kept. That way maybe some people wouldn't just reflex-upvote and actually at least read the abstract...

Re: CRISPR eliminates HIV-1 infection in live animals

#56

Post by sbierwagen »

Animats wrote: post #32

Back in 2011, there was an announcement from MIT about a new approach to a broad-spectrum antiviral that appeared to work.[1] This goes way beyond an AIDS-specific cure. But it was at MIT Lincoln Labs, which doesn't usually do bio. So the researcher moved to Draper Labs, but didn't get much funding. Then that funding ran out. Now the guy behind this is trying to get funding on Indiegogo.[3] The problem seems to be th…

The expensive part of getting a drug to market isn't proving that it can kill cells in a petri dish. Lots of stuff can do that, bleach, hydrogen peroxide...

The expensive part is the clinical trial. You try out the compound in the chemical woodchipper that is the human body, and see what happens. Almost all drugs fail at this point: http://blogs.sciencemag.org/pipeline/archives/2017/01/23/i-d...

>The timing of this report from the FDA is surely no accident, but it’s always a good time to think about this: the great majority of all drugs that enter clinical trials fail. They fail because they don’t do anyone any good, or because what good they might do is outweighed by some serious and unexpected harm. Around 90% of all compounds that start in the clinic never make it out. Even by the time you get to Phase III – and these are drugs that have apparently already worked in sick patients by that point – the failure rate is still nearly 40%. Drug projects fail constantly.

Nobody can predict if a drug will make it through the clinic, and if they say they can, they're lying. There's no way to model it, at all, it's just hugely computationally intractable.

And even if you make it through the first three formal phases of clinical trial, you can get bit in the "fourth" phase: regular patients buying it retail, and maybe dying at statistically higher rates. Consider the Vioxx debacle: https://en.wikipedia.org/wiki/Rofecoxib

>Rofecoxib /ˌrɒfᵻˈkɒksɪb/ is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhea. Rofecoxib was approved by the U.S. Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx.

>On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.[2] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[3] Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and has set aside $4.85bn for legal claims from US citizens.

VC's could spend hundreds of millions on clinical trials for DRACO, make it on the market... and only then discover that it gives patients incurable brain cancer 20 years after they take it.

Re: CRISPR eliminates HIV-1 infection in live animals

#57

Post by jfarlow »

kbenson wrote: post #40
turbohedgehog wrote: post #7

Last time I read about CRISPR used to remove HIV from infected cells, the virus mutated to defeat the CRISPR attack - could this happen here?

Isn't the only way to mutate to avoid CRISPR to change your genes enough that CRISPR can't identify you? If so, doesn't that mean we just find the new genetic signature and generate a variation that targets it? I see CRISPR as grepping through memory for running instruction code. Sure, the code can change, but if you see the behavior, then it's a matter of finding the new code signature manually and generating a new…

Well, as CRISPR was originally found as a kind of immune system, there do exist a number of anti-anti-Cas9 systems against that evolved alongside it. There are a number of small inhibitors of Cas9 [1] (which themselves could be used to tune Cas9 in therapeutics). However up-taking such a defense is admittedly an unlike route for a virus like HIV to take to evolve resistance to a CRISPR-based therapy.

More practically, HIV has such a high mutation rate, that it's likely very difficult to target every HIV sequence with a sequence-specific Cas9 therapy. If the Cas9 guide sequence is too generic it'll take out stuff besides HIV (stuff you need). And if the guide sequence is too specific it won't get all the viral inserts because many are degenerate. As with all things though, 95% success with viral excision via CRISPR, in conjunction with 95% success via immunotherapy [2], and 95% from standard anti-retrovirals [3], get's you pretty good 99.9999% coverage.

That's the power of convergent technologies. It's an interesting slice through a number of modern therapeutic technologies all applied to one of the most challenging of tailored foes. You see convergence of small molecule biochemistry along with immunotherapy, along gene therapy, along with cutting edge synthetic biology - all approaching the problem from different angles.

[1] www.cell.com/cell/fulltext/S0092-8674(16)31683-X

[2] https://serotiny.bio/notes/proteins/ecd4ig/

[3] https://en.wikipedia.org/wiki/Category:Antiretroviral_drugs

Re: CRISPR eliminates HIV-1 infection in live animals

#58

Post by lolive »

rosalinekarr wrote: post #23

For anyone unfamiliar with CRISPR, I strongly recommend this quick introduction video from Kurzgesagt on YouTube: https://www.youtube.com/watch?v=jAhjPd4uNFY

For french users, this basic video describes the principle of CRISPR/CAS9: https://www.youtube.com/watch?v=bYVE05egjPg

Re: CRISPR eliminates HIV-1 infection in live animals

#59

Post by appetizer »

ChuckMcM wrote: post #9

Wow, I had not connected the idea of using CRISPR genome editing with targeting virus dna segments. If I understand the technique correctly (and I am not a biologist for sure!) they used an adeno virus modified with a specific Cas9 setup to elide HIV DNA from cells it infected (normally I associate viruses with adding DNA rather than removing it :-) Is that even close to a correct interpretation? It sounds like the t…

what other purpose did you imagine it for? I guess there are a lot of cool applications but I only knew of the virus modification contexts

Re: CRISPR eliminates HIV-1 infection in live animals

#60

Post by tejtm »

mandude wrote: post #2

Gene therapy (and CRISPR) is ultimately going to eliminate most if not every ailment/issue/genetic problem that we have, including aging and eye problems. Very thankful we are reaching the point where we can go into our cells and fix ourselves.

I do agree, but that is just the good news. In other news although we can harbor optimistic thoughts for scientists, medical professionals, lawmakers and maybe even politicians all around the globe to do the "right" thing to preserve human life in a currently recognizable form, but there is not a force on heaven or earth that is going to stop parents from trying to give their children every advantage.
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