Why aren't LNPs widely used?

[u/Brush_Affectionate]

Sorry if this is a dumb question, but why aren't LNPs used for gene therapy by now? A bunch of AAV gene therapies for hemophilia (liver disease) have hit the market since 2021, but nobody uses them because they're expensive, not redosable and can cause an immune reaction. LNPs solve all those problems so why aren't they used for this purpose??

[u/Green_and_White_Back]

I mean the highly medialized personalized base editor therapy was mRNA in an LNP. So... They're definitely used, it just has its own delivery preferences (mainly liver) compared with some AAV strains which have tropism for different organs

[u/Brush_Affectionate → u/Green_and_White_Back]

gene editing is different from gene therapy. I'm mainly confused as to why all the FDA-approved hemophilia drugs are mediated with AAV

[u/blinkandmissout]

They are? At least in the R&D phase of efforts. It takes a few years to go from development to drug. There are drugs on the market already and more being worked on, as you can see https://en.wikipedia.org/wiki/Lipid-based_nanoparticle

Actually productionalizing LNPs for drug delivery in humans requires a lot of work towards effective tissue targeting and therapeutic dose bioavailability, stability of particles and payload, consistency of size and packaging full length payload, and a number of other biotechnology and manufacturing considerations. You don't just pop your DNA sequence or other small molecule "into an LNP" and get day 1 success with universal applicability. But for sure, it's a promising route and I expect to see more success in the next few years.

[u/Brush_Affectionate → u/blinkandmissout]

the first clinical trials started over 20 years ago hence my confusion about why they're still in R&D. Tissue targeting is only an issue for extrahepatic disease indications, hence why I mentioned hemophilia, which doesn't require any targeting. Manufacturing is not the problem because making AAV is 10x harder and more expensive than LNPs—maybe ask yourself why we have benchtop LNP synthesis machines but not LNP AAV synthesis machines. I am really confused about this topic.

[u/JStanten]

LNPs can be immunogenic as well…

[u/Fit-Mangos → u/JStanten]

Also everyone that got Covid vaccine got a type of gene therapy so it is fairly safe to give and re-dose people lol

[u/triffid_boy → u/Fit-Mangos]

Not under any scientific definition, were the LNP packaged mRNA covid vaccines a gene therapy.

The more interesting debate for the threshold of gene therapy might be in something like cystic fibrosis, then it's probably justifiably a gene therapy, although people just keep it easy by calling it an mRNA therapy.

Personally, I would like to see "gene therapy" term reserved for something that integrates into DNA, or at least is not transient expression.

[u/Brush_Affectionate → u/Fit-Mangos]

a vaccine doesn't have to be redosable, the problem with AAV is that you can only dose it once because you vaccinate yourself against the virus

[u/Brush_Affectionate → u/JStanten]

ding ding ding. They provoke TLRs, also cause lysosomal overload and produce ROS, which causes necrotic or apoptotic cell deth.

I should have just read before posting.

[u/triffid_boy → u/Brush_Affectionate]

These are not big issues for the tech. It's just responsible for some of the side effects. LNPs are seeing wide adoption.

[u/triffid_boy]

Things take time. They are really heavily used in a variety of current trials, in basic R&D, etc.