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CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

innovativegenomics.org

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Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#61

Post by perlgeek »

ordinaryradical wrote: post #32

CRISPR is an extremely overhyped approach which found a marketing engine via popular science. There is 1 FDA approved CRISPR therapy as compared to 7 for AAV and 7 for Lentivirus. Counting all viral vector therapies that have been approved, we’re sitting at 19 approved therapies versus 1 for CRISPR. I think CRISPR ideas in a lab are just an easy way into the mainstream press, but viral vector delivery is the real fut…

CRISPR is foremost a research tool. Calling it "extremely overhyped" without restricting it medical treatment seems disingenuous.

The CRISPR-Cas9 gene-editing tool was developed in 2012, so I don't find it surprising that merely 14 years later, there's only one approved treatment. From discovery to approval, drug development often takes 10-15 years, and often much longer for novel techniques. So I'd say it too early to call it overhyped for treatments.

Finally, I think we'll see a lot of treatments that don't use CRISPR-Cas9, but related gene editing techniques, but it'll take another 10 to 20 years.

Take a look at https://en.wikipedia.org/wiki/MRNA_vaccine#History for how long another novel technique has been in development before it became really widespread with the mrna-based covid-19 vaccines.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#62

Post by spligak »

GaggiX wrote: post #56
spligak wrote: post #50

Earlier quoted context omitted.

You're correct about CRISPR Cas9. The off-target affects are difficult to manage. The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell. The implications of Cas12a2…

I know nothing about this field, but I imagine the actual problem is how do you deliver the Cas12a2 protein to each individual cancer cell compare to a viral gene therapy?

There are two major problems, delivery is one of them. Collateral damage of mass cell destruction leading to systemic inflammation is the other.

The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet.

The collateral damage problem is the backpressure on the delivery problem. If you get really good at delivery, you can destroy A LOT of cells very quickly. The human body (usually) responds to these events by releasing a lot of pro-inflammatory cytokines. This can lead to cytokine storms or worse.

As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#63

Post by Gethsemane »

spligak wrote: post #50
ordinaryradical wrote: post #32

CRISPR is an extremely overhyped approach which found a marketing engine via popular science. There is 1 FDA approved CRISPR therapy as compared to 7 for AAV and 7 for Lentivirus. Counting all viral vector therapies that have been approved, we’re sitting at 19 approved therapies versus 1 for CRISPR. I think CRISPR ideas in a lab are just an easy way into the mainstream press, but viral vector delivery is the real fut…

You're correct about CRISPR Cas9. The off-target affects are difficult to manage. The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell. The implications of Cas12a2…

Have you written about your experience anywhere? It would be interesting to see how you approached the research sector as a layperson. Are there any plans to move to in vivo? Best of luck with your research!

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#64

Post by ben_w »

dylan604 wrote: post #14
arcticfox wrote: post #3

Earlier quoted context omitted.

I'm pretty optimistic. I think it's a threshold question where we need a number of basic technologies to all get over certain bars before the floodgates start to open. Over the past 1-2 decades there has been unbelievable progress at the basic technology level but most people are unimpressed because they haven't translated yet due to not individually being sufficient to cause an explosion of progress. IMO, we're star…

So we're waiting for the Apple of the medical world to take a bunch of preexisting things to be applied together in a way that makes the whole much more valuable than the pieces. Or we need all of the individual lions to come together to make the Voltron?

Usually it takes about a decade for most medical inventions to work their way through medical bureaucracy[0], so I'd say that 10 years ago we were at the stage of watching Matthew Broderick war-dialling with an acoustic coupler and reading Usborne Books telling us that criminals of the future would work from home, and today we're in the exciting early days of dialup, AltaVista, and GeoCities[1].

[0] The covid vaccines collectively were faster only due to the fact that when money is no object you can parallelise a lot of options and can pipeline the testing stages rather than waiting for full review and another funding round before progressing to the next stage

[1] Where they-don't-tile-but-we-did-it-anyway animated gif backgrounds are the metaphor for home kits to make random things bioluminescent: https://www.the-odin.com/gfp-bacteria/

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#66

Post by tjpnz »

sssilver wrote: post #5

What economic / political model would cause the society to prioritize this over adtech? It seems so unsettling that brilliant human minds are trying hard, every day, to figure out how to make it impossible to bypass watching ads on YouTube, instead of helping cure cancer.

>brilliant human minds are trying hard, every day, to figure out how to make it impossible to bypass watching ads on YouTube, instead of helping cure cancer.

And even more brilliant minds are defeating it, every day. I have doubts about how useful they would be in a research lab.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#67

Post by im3w1l »

spligak wrote: post #62
GaggiX wrote: post #56

Earlier quoted context omitted.

I know nothing about this field, but I imagine the actual problem is how do you deliver the Cas12a2 protein to each individual cancer cell compare to a viral gene therapy?

There are two major problems, delivery is one of them. Collateral damage of mass cell destruction leading to systemic inflammation is the other. The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet. The collater…

Naively, I would deal with this by deciding how many cells I want to kill each day and then figure out a dosing schedule that achieves that. Or maybe it's better to do one dose every few days. But yeah either way.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#68

Post by shevy-java »

spligak wrote: post #50
ordinaryradical wrote: post #32

CRISPR is an extremely overhyped approach which found a marketing engine via popular science. There is 1 FDA approved CRISPR therapy as compared to 7 for AAV and 7 for Lentivirus. Counting all viral vector therapies that have been approved, we’re sitting at 19 approved therapies versus 1 for CRISPR. I think CRISPR ideas in a lab are just an easy way into the mainstream press, but viral vector delivery is the real fut…

You're correct about CRISPR Cas9. The off-target affects are difficult to manage. The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell. The implications of Cas12a2…

So how does Cas12a2 mitigate off-target effects?

If it were to work, gene therapy as-is would be possible. Which it is not, not even for those overpriced therapies. I have no doubt that sooner or later it will happen, as the problem space is finite, not infinite, but I simply don't see the correlation here.

> The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound.

So what does this change exactly? Humans defined it as "undruggable conditions". You can reason this is an improvement, but I still see it in failure-territory. If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.

> I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.

How does "answering questions" offset the technology being inferior right now?

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#69

Post by shevy-java »

spligak wrote: post #62
GaggiX wrote: post #56

Earlier quoted context omitted.

I know nothing about this field, but I imagine the actual problem is how do you deliver the Cas12a2 protein to each individual cancer cell compare to a viral gene therapy?

There are two major problems, delivery is one of them. Collateral damage of mass cell destruction leading to systemic inflammation is the other. The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet. The collater…

Lipid nanoparticles are quite old as-is. How do you target cells specifically?

> If you get really good at delivery, you can destroy A LOT of cells very quickly.

You can destroy cells quickly. Ok. So the question is: how do you detect specifically only cancer cells via lipid nanoparticles? That was already a problem years ago with Herceptin. The rationale that is always used is that "we need to do something" for certain aggressive cancers. It has never been a super-effective technique, despite all the promo of how monoclonal antibodies are so accurate.

> As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.

That's already the status quo in the whole cancer field. I don't think that more than sloppy accuracy is acceptable for any gene therapy - and the off-target cleaving of CRISPR has always been the number #1 problem here.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#70

Post by MontyCarloHall »

The idea of using CRISPR/Cas to detect tumor-specific mutations that aren't necessarily oncogenic and then kill the cell is not a new one [0, 1, 2]. However, previous studies used Cas9, which just damages the DNA at the target site; this uses Cas12a2, which is far more destructive because it shreds the chromatin in the cell once activated by detecting the target sequence.

As with any cancer treatment, it's likely the tumor will evolve resistance. My guess is that cells will find ways to reject the lipid nanoparticles used to deliver the CRISPR/Cas mRNA and associated guide sequence(s), either via modifications to the cell surface (preventing LNP uptake) or via changes to endosomal/lysosomal pathways (causing the mRNA payload to get degraded before it has a chance to be translated into protein).

[0] https://pubmed.ncbi.nlm.nih.gov/28575452/

[1] https://www.nature.com/articles/s41598-018-30205-2

[2] https://www.nature.com/articles/s41467-020-18875-x

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