I spoke with one of the inventors of bridge recombinases at a dinner a few months ago and (at least according to him), they work in human cells.
I haven’t verified this independently in my lab, but it’s at least one data point.
On a broader note, I find the whole field of gene therapy very confusing. In many cases it seems like there are exceptionally powerful tools that are being ignored in favor of sloppy, dangerous, imprecise alternatives.
Why are we still using lentiviral vectors to insert working copies of genes when we can usually just fix the broken gene using prime editors?
You look at gene therapies like Casgevy for sickle cell and they just make no fucking sense.
Sickle cell is predominantly cause by an adenine to thymine swap at the sixth codon in the HBB gene. Literally one letter change at a very well known spot in one protein.
You’d think this would be a perfect use case for gene editing, right? Just swap out that letter and call it a day!
But no. This is not how Casgevy works. Instead, Casgevy works by essentially flipping a switch to make the body stop producing adult hemoglobin and start producing fetal hemoglobin.
Fetal hemoglobin doesn’t sickle, so this fixes sickle cell. But like… why? Why not just change the letter that’s causing all the problems in the first place?
It’s because they’re using old school Cas9. And old school Cas9 editing is primarily used to break things by chopping them in half and relying on sloppy cellular repair processes like non-homologous end joining to stitch the DNA back together in a half-assed way that breaks whatever protein is being produced.
And that’s exactly what Casgevy does; it uses Cas9 to induce a double stranded break in BCL11A, a zinc finger transcription factor that normally makes the cells produce adult hemoglobin instead of the fetal version. Once BCL11A is broken, the cells start producing fetal hemoglobin again.
But again...
Why?
Prime editors are very good at targeting the base pair swap needed to fix sickle cell. They’ve been around for SIX YEARS. They havery extremely low rates of off-target editing. Their editing efficiency is on-par with that of old-school Cas9. And they have lower rates of insertion and deletion errors near the edit site. So why don’t we just FIX the broken base pair instead of this goofy work-around?
Yet the only thing I can find online about using them for sickle cell is a single line announcement from Beam Therapeutics that vaguely referecing a partnership with prime medicine that MIGHT use them for sickle cell.
This isn’t an isolated incident either. You go to conferences on gene editing and literally 80% of academic research is still using sloppy double strand breaking Cas9 to do editing. It’s like if all the electric car manufacturers decided to use lead acid batteries instead of lithium ion.
It’s just too slow. Everything is too fucking slow. It takes almost a decade to get something from proof of concept to commercial product.
This, more than anything, is why I hope special economic zones like Prospera win. You can take a therapy from animal demonstration to commercial product in less than a year for $500k-$1 mil. If we had something like that in the US there would be literally 10-100x more therapeutics available.
I spoke with one of the inventors of bridge recombinases at a dinner a few months ago and (at least according to him), they work in human cells.
I haven’t verified this independently in my lab, but it’s at least one data point.
On a broader note, I find the whole field of gene therapy very confusing. In many cases it seems like there are exceptionally powerful tools that are being ignored in favor of sloppy, dangerous, imprecise alternatives.
Why are we still using lentiviral vectors to insert working copies of genes when we can usually just fix the broken gene using prime editors?
You look at gene therapies like Casgevy for sickle cell and they just make no fucking sense.
Sickle cell is predominantly cause by an adenine to thymine swap at the sixth codon in the HBB gene. Literally one letter change at a very well known spot in one protein.
You’d think this would be a perfect use case for gene editing, right? Just swap out that letter and call it a day!
But no. This is not how Casgevy works. Instead, Casgevy works by essentially flipping a switch to make the body stop producing adult hemoglobin and start producing fetal hemoglobin.
Fetal hemoglobin doesn’t sickle, so this fixes sickle cell. But like… why? Why not just change the letter that’s causing all the problems in the first place?
It’s because they’re using old school Cas9. And old school Cas9 editing is primarily used to break things by chopping them in half and relying on sloppy cellular repair processes like non-homologous end joining to stitch the DNA back together in a half-assed way that breaks whatever protein is being produced.
And that’s exactly what Casgevy does; it uses Cas9 to induce a double stranded break in BCL11A, a zinc finger transcription factor that normally makes the cells produce adult hemoglobin instead of the fetal version. Once BCL11A is broken, the cells start producing fetal hemoglobin again.
But again...
Why?
Prime editors are very good at targeting the base pair swap needed to fix sickle cell. They’ve been around for SIX YEARS. They havery extremely low rates of off-target editing. Their editing efficiency is on-par with that of old-school Cas9. And they have lower rates of insertion and deletion errors near the edit site. So why don’t we just FIX the broken base pair instead of this goofy work-around?
Yet the only thing I can find online about using them for sickle cell is a single line announcement from Beam Therapeutics that vaguely referecing a partnership with prime medicine that MIGHT use them for sickle cell.
This isn’t an isolated incident either. You go to conferences on gene editing and literally 80% of academic research is still using sloppy double strand breaking Cas9 to do editing. It’s like if all the electric car manufacturers decided to use lead acid batteries instead of lithium ion.
It’s just too slow. Everything is too fucking slow. It takes almost a decade to get something from proof of concept to commercial product.
This, more than anything, is why I hope special economic zones like Prospera win. You can take a therapy from animal demonstration to commercial product in less than a year for $500k-$1 mil. If we had something like that in the US there would be literally 10-100x more therapeutics available.
Hmm. I don’t believe that, not without a bit more evidence.