"The other problem is with viral vector based gene therapy is you can’t have it again. You develop antibodies which prevent it from working again, and it could
cause a dangerous immune response."
Just wondering - would it make sense to immune-suppress the patient for a short period of administering of the viral-based therapy.
And as they describe that most gene therapies affect only extra-nuclear DNA, and thus have no permanent effect, wouldn't mRNA work better then in such cases - naturally the tech wasn't there 10+ years ago, yet today thanks to COVID it is here.
Edit (due to posting rate limit) in response to comment below:
I was thinking about mRNA coding dystrophin like it was coding COVID protein - should be cheap and easy (well, for some definition of easy in that context) doable, and it would be like a weekly self-injection - no toxicity, etc. Of course fixing the issue once for life would be better, once such cure becomes available, yet for now it would be similar like diabetics have with insulin - hassle for sure, yet it works.
AAV based therapies may have no permanent effect when the cells in question are actively proliferating (and the payload dilutes with each division) but muscle tissue is largely post-mitotic.
mRNA is in comparison very transient (in the range of days, and that's being charitable), even when modified (5' cap, uridine analogs, poly(A) tail) as it was in COVID vaccines. This is fine for vaccines, as you essentially want just a single exposure to the protein with each vaccine dose. You do need dystrophin continuously though (even though the cells are not dividing much, they are still recycling it).
You could argue for delivering gene therapy with mRNA/NLPs in multiple doses over the course of patient's life but that would likely 1) exacerbate toxicity and 2) be super-expensive
Do we have any studies that show this fast clearance? From what I understand at least one of them used a pseudo-uradine that there isn't an efficient direct metabolic pathway to process, which was kind of the whole point. The idea being it would circulate longer and be "more effective"
The uridine modification was intended to reduce immunogenicity of mRNA - some of our immune cells have pattern-seeking receptors in the TLR family that recognize ssRNA and dsRNA. The presence of modified uridines throws this pattern recognition off. (https://doi.org/10.1016/j.jconrel.2015.08.051)
The modifications to increase mRNA half-life concerned mostly the caps and poly(A) tail. But even with those the persistence was in the range of days (sort of depending on how sensitive a method you picked).
That's right, they use N1-Methylpseudouridine instead of uridine (the nucleoside contained in uracil, which is the U in mRNA sequences) to last a bit longer (but not forever) and to avoid triggering immune reactions to the mRNA itself (the immune system can detect foreign mRNA).
Certainly the vaccine's mRNA sequence breaks down into separate nucleotides. If it did not, continued production of the antigens would cause a chronic immune reaction and/or immune exhaustion that would make the vaccine ineffective.
I don't know what happens to the N1-Methylpseudouridine though. That's an interesting question.
> Certainly the vaccine's mRNA sequence breaks down into separate nucleotides. If it did not, continued production of the antigens would cause a chronic immune reaction and/or immune exhaustion that would make the vaccine ineffective.
I suspect you just described "long COVID" or "vaccine injury" for some fraction of folks.
Now, that particular study is in whatever cell line, highly dubious how it pertains to a human body, a few steps removed. But if you say "will you see this if you vaccinate 500 million times in 500 million people each with 500 trillion cells" - yea probably you would
Numerous studies have found vax-derived spike persisting for months and even years after vaccination, giving rise to concerns expression of spike can continue long after the claimed 24-48 hours.
A recent study found spike protein persisting for 17 months in the cerebral arteries of stroke victims. [1]
> In our study, in situ hybridization detected both mRNA derived from the vaccine and mRNA from the SARS-CoV-2 virus. ... our in situ hybridization method has high sensitivity and could detect trace amounts of mRNA, possibly reflecting unrecognized asymptomatic infections. These findings emphasize the need for caution in interpreting the presence of spike protein as exclusively vaccine-related.
We should also note that the study doesn't show that the original vaccine mRNA somehow survived for months, only that mRNA matching the vaccine sequence was detected by complementary probes.
I wonder if, in these cases, the vaccine was administered to someone with an active (but asymptomatic) COVID infection, and the vaccine mRNA was copied by the same RNA-dependent RNA polymerase that copies the viral RNA.
That might explain why both vaccine and viral RNA were found.
"The other problem is with viral vector based gene therapy is you can’t have it again. You develop antibodies which prevent it from working again, and it could cause a dangerous immune response."
Just wondering - would it make sense to immune-suppress the patient for a short period of administering of the viral-based therapy.
And as they describe that most gene therapies affect only extra-nuclear DNA, and thus have no permanent effect, wouldn't mRNA work better then in such cases - naturally the tech wasn't there 10+ years ago, yet today thanks to COVID it is here.
Edit (due to posting rate limit) in response to comment below:
I was thinking about mRNA coding dystrophin like it was coding COVID protein - should be cheap and easy (well, for some definition of easy in that context) doable, and it would be like a weekly self-injection - no toxicity, etc. Of course fixing the issue once for life would be better, once such cure becomes available, yet for now it would be similar like diabetics have with insulin - hassle for sure, yet it works.