I might end up eating my words on the delivery problem. Something has just come out a few days ago that renewed a bit of my optimism, see here. According to the findings in this pre-print, it is possible to shield AAVs from the immune system using protein vaults that the immune system recognizes as self. It is not perfect though; although VAAV results in improved transduction efficiency even in the presence of neutralizing antibodies, it still only results in transduction of ~4% of cells if neutralizing antibodies are present. This means you’d need to cross your fingers and hope that 1) the patient doesn’t already have naturally extant neutralizing antibodies and 2) they don’t develop them over the course of the hundreds/thousands of VAAV you’re going to give them. In the paper, it is stated that AAV gets packaged in the vaults only to an extent rather than completely. So, more than likely, even if you’re injecting 99% VAAV and 1% naked AAV, if you do this 100 times you are almost sure to develop neutralizing antibodies to that 1% of naked AAV (unless they have a way to completely purify VAAV that removes all naked AAV). One way to combat the transduction problem post-innocuation though is using multiple injections of the same edit in order to approximate 100% transduction, though I’m pessimistic that this will work because there is probably a good reason that only 4% of cells were transducible; something might be different about them than the rest of cells, so you might receive diminishing transduction returns with each injection. They also still need to demonstrate that these work in vivo and that they can be routed to the CNS. Nonetheless, I’m excited to see how this shakes out.
I might end up eating my words on the delivery problem. Something has just come out a few days ago that renewed a bit of my optimism, see here. According to the findings in this pre-print, it is possible to shield AAVs from the immune system using protein vaults that the immune system recognizes as self. It is not perfect though; although VAAV results in improved transduction efficiency even in the presence of neutralizing antibodies, it still only results in transduction of ~4% of cells if neutralizing antibodies are present. This means you’d need to cross your fingers and hope that 1) the patient doesn’t already have naturally extant neutralizing antibodies and 2) they don’t develop them over the course of the hundreds/thousands of VAAV you’re going to give them. In the paper, it is stated that AAV gets packaged in the vaults only to an extent rather than completely. So, more than likely, even if you’re injecting 99% VAAV and 1% naked AAV, if you do this 100 times you are almost sure to develop neutralizing antibodies to that 1% of naked AAV (unless they have a way to completely purify VAAV that removes all naked AAV). One way to combat the transduction problem post-innocuation though is using multiple injections of the same edit in order to approximate 100% transduction, though I’m pessimistic that this will work because there is probably a good reason that only 4% of cells were transducible; something might be different about them than the rest of cells, so you might receive diminishing transduction returns with each injection. They also still need to demonstrate that these work in vivo and that they can be routed to the CNS. Nonetheless, I’m excited to see how this shakes out.