3 ms·

crispr 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 interest

crispr 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 ago
How 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 ago
  According 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 ago
Your 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 ago
    We 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.
- AllegedAlec 3y ago
  > Your point is broadly correct (not sure about disability though), but I think it overstates the danger of what will happen in practice https://www.nature.com/articles/nrc1122 https://www.nature.com/articles/nrc1122
- amluto 3y ago
  One thing I was confused by: why did Vertex choose to reactivate HbF instead of attempting to correct the mutation that causes sickle cell disease in the first place?
  - 3y ago

crispr 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 ago

How 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 ago
According 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 ago

Your 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 ago
  We 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.
AllegedAlec 3y ago
> Your point is broadly correct (not sure about disability though), but I think it overstates the danger of what will happen in practice https://www.nature.com/articles/nrc1122 https://www.nature.com/articles/nrc1122
amluto 3y ago
One thing I was confused by: why did Vertex choose to reactivate HbF instead of attempting to correct the mutation that causes sickle cell disease in the first place?
- 3y ago