One thing I don’t understand: you write that a major problem with viruses is:
As one might expect, the immune system is not a big fan of viruses. So when you deliver DNA for a gene editor with an AAV, the viral proteins often trigger an adaptive immune response. This means that when you next try to deliver a payload with the same AAV, antibodies created during the first dose will bind to and destroy most of them.
Is this a problem for people who expect to only want one genetic modification during their lifetime?
One is a concern for people who are getting a single dose monogenic gene therapy who already have antibodies to an AAV delivery vector due to a natural infection. In these cases, doctors can sometimes switch the therapy to use an AAV with a different serotype that can’t be attacked by the patient’s existing antibodies. If that’s not available, they’ll sometimes give patients immunosupressants.
The problem is more relevant in the context of multiplex editing because you may not be able to make all the edits you’d like to in one round of therapy. You can only inject so many AAVs or lipid nanoparticles or what have you at a time. Cells only have a limited capacity to process and break down editor proteins, and other waste products of the editing process. So you may need to do multiple editing rounds to achieve the desired effect.
It will be a lot easier to do this if the delivery vector itself doesn’t trigger the immune system. If it does, antibodies formed during the first round of edits will attack and destroy the the delivery vector. Maybe you can just give someone immunosupressants during each round of treatment? Or maybe you can just use a different AAV? There are potential solutions but I don’t yet know which are likely to work best.
Repeat administration is a problem for traditional gene therapy too, since the introduced gene will often be eliminated rather than integrated into the host genome.
Thanks, this is very interesting.
One thing I don’t understand: you write that a major problem with viruses is:
Is this a problem for people who expect to only want one genetic modification during their lifetime?
So there are two separate concerns:
One is a concern for people who are getting a single dose monogenic gene therapy who already have antibodies to an AAV delivery vector due to a natural infection. In these cases, doctors can sometimes switch the therapy to use an AAV with a different serotype that can’t be attacked by the patient’s existing antibodies. If that’s not available, they’ll sometimes give patients immunosupressants.
The problem is more relevant in the context of multiplex editing because you may not be able to make all the edits you’d like to in one round of therapy. You can only inject so many AAVs or lipid nanoparticles or what have you at a time. Cells only have a limited capacity to process and break down editor proteins, and other waste products of the editing process. So you may need to do multiple editing rounds to achieve the desired effect.
It will be a lot easier to do this if the delivery vector itself doesn’t trigger the immune system. If it does, antibodies formed during the first round of edits will attack and destroy the the delivery vector. Maybe you can just give someone immunosupressants during each round of treatment? Or maybe you can just use a different AAV? There are potential solutions but I don’t yet know which are likely to work best.
Repeat administration is a problem for traditional gene therapy too, since the introduced gene will often be eliminated rather than integrated into the host genome.