I saw it clearly with the tolerance of Adenylyl cyclase and apparently it is necessary to prevent it. It is as strong as the tolerance of the receptor and therefore with DREADD tolerance is not resolved but only the side effects of MDMA that derive from the lack of selectivity are resolved. This means that MDMAv2 relies totally on stem cells to resolve the tolerance of the whole cell and it is not possible to do without it...Growing stem cells into neurons is fairly hard. I have direct experience using cas9 to edit induced pluripotent stem cells, and differentiating them to study disease states in a different organ, and the workflow is like 4 months of daily culture and procedures to get a single indel (which can be pretty non specific, as long as a frame shift is induced to disrupt the gene).
Typically differentiation to specific cell types is fairly finnicky (think a 96 well plate, so that a high failure rate is acceptable).
Stem cells have a lot of quirks when it comes to lentiviral infection, you need to use weak promoters, as they silence viruses with strong promoters like cmv.
I actually think germline editing would be a more robust approach, as you would have the potential to alter pre-exisiting circuits, rather than having a population added into the brain to give the effect.
Serotonergic signaling is very circuit dependant, often you can stimulate very small populations of neurons to get an effect. Opioid withdrawal is tied a lot more to an innapropriate immune response from microglia, which a generalized stem cell infusion has a better chance of treating non specifically.
UPDATE: lol it is possible to engineer dreadds to not sensitize Adenylyl cyclase https://sci-hub.do/https://www.sciencedirect.com/science/article/abs/pii/S0014299915300133
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