Thanks for leaving such a high quality comment. I’m sorry for taking so long to get back to you.
We fully expect bringing this to market to take tens of millions of dollars. My best guess was $20-$40 million.
My biggest concern is your step 1:
“Determine if it is possible to perform a large number of edits in cell culture with reasonable editing efficiency and low rates of off-target edits.”
And translating that into step 2:
“Run trials in mice. Try out different delivery vectors. See if you can get any of them to work on an actual animal.”
I would like to hear more about your research into approaching this problem, but without more information, I am concerned you may be underestimating the difficulty of successfully delivering genetic material to any significant number of cells.
We expect this to be difficult, but we DON’T expect to have to solve the delivery problem entirely on our own. There are significant incentives for existing companies such as Dyno Therapeutics to solve the problem of delivering genes (or other payloads) to the nucleus of brain cells. In fact, Dyno already has a product, Dyno bCap 1 which successfully delivered genes to between 5% and 20% of brain cells in non-human primates.
Obviously we will need higher efficiencies than that to perform edits for polygenic brain diseases or intelligence, but the ease of delivering payloads to brain cells has been gradually improving over the years and I expect it to continue doing so.
There are of course some issues:
I know from some conversations with a former employee of Dyno that the capsids can be customized to be serologically distinct so that any antibodies formed in response to one round of treatment will not destroy the capsids used in the second round. But I am still waiting to hear back from them regarding the cost and time required to do this sort of customization.
Custom AAVs are also quite expensive per dose, largely due to the cost of reagents and other basic supplies that no one has figured out how to make cheaper yet. So it’s a plausible delivery mechanism, but far from ideal.
Still, the fact that there is an existing product on the marketplace which can get custom DNA payloads into the nuclei of brain cells gives me hope that someone else will have made major headway on the delivery problem by the time we are ready for trials in cows or non-human primates.
In the meantime, we simply need a way to get editors into HEK cells and brain cells efficiently in cell cultures to test multiplex editing approaches. I’m sure this will pose its own set of challenges, but given dozens of labs have done this I don’t expect that to be infeasible.
Send me an email if you have time to chat about this. If you’re willing I’d like to pick your brain more about other aspects of the project.
Thanks for leaving such a high quality comment. I’m sorry for taking so long to get back to you.
We fully expect bringing this to market to take tens of millions of dollars. My best guess was $20-$40 million.
We expect this to be difficult, but we DON’T expect to have to solve the delivery problem entirely on our own. There are significant incentives for existing companies such as Dyno Therapeutics to solve the problem of delivering genes (or other payloads) to the nucleus of brain cells. In fact, Dyno already has a product, Dyno bCap 1 which successfully delivered genes to between 5% and 20% of brain cells in non-human primates.
Obviously we will need higher efficiencies than that to perform edits for polygenic brain diseases or intelligence, but the ease of delivering payloads to brain cells has been gradually improving over the years and I expect it to continue doing so.
There are of course some issues:
I know from some conversations with a former employee of Dyno that the capsids can be customized to be serologically distinct so that any antibodies formed in response to one round of treatment will not destroy the capsids used in the second round. But I am still waiting to hear back from them regarding the cost and time required to do this sort of customization.
Custom AAVs are also quite expensive per dose, largely due to the cost of reagents and other basic supplies that no one has figured out how to make cheaper yet. So it’s a plausible delivery mechanism, but far from ideal.
Still, the fact that there is an existing product on the marketplace which can get custom DNA payloads into the nuclei of brain cells gives me hope that someone else will have made major headway on the delivery problem by the time we are ready for trials in cows or non-human primates.
In the meantime, we simply need a way to get editors into HEK cells and brain cells efficiently in cell cultures to test multiplex editing approaches. I’m sure this will pose its own set of challenges, but given dozens of labs have done this I don’t expect that to be infeasible.
Send me an email if you have time to chat about this. If you’re willing I’d like to pick your brain more about other aspects of the project.