From my conversations with people working on delivery vector, I’d guess you can probably get 20-40% with current AAVs and probably less with current lipid nanoparticles.
But that percentage has been increasing over time, and I suspect it will continue to do so. That’s why I estimated that brain cells would, on average, receive 50% of the edits we attempt to make; by the time we’re ready to do animal trials that is probably roughly where we’ll be at.
Are edits somehow targeted at brain cells in particular or do they run throughout the body?
This is addressed in the post, but I understand that many people may not have read the whole thing because it’s so long.
The set of cells that will be targeted depends on the delivery vector and on how it is customized. You can add custom peptides to both AAVs and lipid nanoparticles which will result in their uptake by a subset of tissues in the body.
Most of the ones I have looked at are taken up by several tissues among which is the brain. This is probably fine, but as stated in the appendix there’s a chance expression of Cas9 proteins in non-target tissues will trigger the adaptive immune system.
If that did turn out to be a big issue, there are potential solutions which I only briefly touched on in the post. One is to just give someone an immunosuppressant for a few days while the editor proteins are floating around in the body. Another is to selectively express the editors in a specific tissue as specified by the mRNA transcribed uniquely in that cell type.
The latter would be a general purpose solution to avoiding any edits in any tissues except the target type, but would reduce efficiency. So not something that would be desirable unless it’s necessary.
What’s your best guess for what percentage of cells (in the brain) receive edits?
Are edits somehow targeted at brain cells in particular or do they run throughout the body?
From my conversations with people working on delivery vector, I’d guess you can probably get 20-40% with current AAVs and probably less with current lipid nanoparticles.
But that percentage has been increasing over time, and I suspect it will continue to do so. That’s why I estimated that brain cells would, on average, receive 50% of the edits we attempt to make; by the time we’re ready to do animal trials that is probably roughly where we’ll be at.
This is addressed in the post, but I understand that many people may not have read the whole thing because it’s so long.
The set of cells that will be targeted depends on the delivery vector and on how it is customized. You can add custom peptides to both AAVs and lipid nanoparticles which will result in their uptake by a subset of tissues in the body.
Most of the ones I have looked at are taken up by several tissues among which is the brain. This is probably fine, but as stated in the appendix there’s a chance expression of Cas9 proteins in non-target tissues will trigger the adaptive immune system.
If that did turn out to be a big issue, there are potential solutions which I only briefly touched on in the post. One is to just give someone an immunosuppressant for a few days while the editor proteins are floating around in the body. Another is to selectively express the editors in a specific tissue as specified by the mRNA transcribed uniquely in that cell type.
The latter would be a general purpose solution to avoiding any edits in any tissues except the target type, but would reduce efficiency. So not something that would be desirable unless it’s necessary.