Somatic gene editing was in cards for a while now, but I assumed that so far off-target effects would make that pretty risky, especially for a large number of variants.
What is the current situation regarding off-target effects for large numbers of edits?
The next question would be the success-rate. Even successful somatic gene editing I’ve read about so far have modified only a small fraction of cells. Is it realistic to modify a double digit percentage of neurons in the brain?
I believe it is at least plausible that we should be able to do this. We have examples of mouse studies where they’ve modified autism-associated genes and showed significant reductions of behavioral issues. It looks like they were able to modify a particular gene in about 39% of the cells (86% for the treatment samples vs 49% for the control sample).
I suspect we could increase the efficiency to edit a greater proportion of the cells.
I do this this technological hurdle can be overcome with sufficient research effort. Do note that part of the challenge of somatic editing of human brain cells is the absolute number of cells to be edited, and the volume of space those cells occupy, which are exponentially different in large human brains vs small mouse brains. These factors trade off against things like immune response time, which doesn’t vary based on brain size. So yeah, the challenge in a human-size brain will be bigger. How much bigger? I dunno. Still, I absolutely think it makes sense to start with small cheap animal models like mice and juvenile zebrafish, and then move into larger models like pigs.
Somatic gene editing was in cards for a while now, but I assumed that so far off-target effects would make that pretty risky, especially for a large number of variants.
What is the current situation regarding off-target effects for large numbers of edits?
Significantly better due to base editors and prime editors, neither of which induce double-stranded breaks
The next question would be the success-rate. Even successful somatic gene editing I’ve read about so far have modified only a small fraction of cells. Is it realistic to modify a double digit percentage of neurons in the brain?
I believe it is at least plausible that we should be able to do this. We have examples of mouse studies where they’ve modified autism-associated genes and showed significant reductions of behavioral issues. It looks like they were able to modify a particular gene in about 39% of the cells (86% for the treatment samples vs 49% for the control sample).
I suspect we could increase the efficiency to edit a greater proportion of the cells.
I do this this technological hurdle can be overcome with sufficient research effort. Do note that part of the challenge of somatic editing of human brain cells is the absolute number of cells to be edited, and the volume of space those cells occupy, which are exponentially different in large human brains vs small mouse brains. These factors trade off against things like immune response time, which doesn’t vary based on brain size. So yeah, the challenge in a human-size brain will be bigger. How much bigger? I dunno. Still, I absolutely think it makes sense to start with small cheap animal models like mice and juvenile zebrafish, and then move into larger models like pigs.