As for the CNS - Voyager therapeutics has had some great readouts in September in gene therapy for Parkinson's. More data coming out in Q1 to see second part of study.
its still pretty hard from what i can tell to deliver oligos to specific cells. delivery has been a huge challenge for ASOs, mRNA etc. viral vectors and autologous cell therapies have been used but have limitations, and antibody-tagged "targeted" nanoparticles have also been tried with varying degrees of success.
theres been some really clever developments in delivering oligos with cationic lipid nanoparticles to macrophages. biontech has an approach where theyve made nanoparticles that are naturally taken up by macropinocytosis by dendritic cells and macrophages. if you get the overall charge of the nanoparticle right (net negative i believe), the dendritic cells migrate to the spleen (rather than the lung with positive charge), where they can present antigen encoded with mRNA to t cells. they also have some interesting mRNA tech that increases the transfection efficiency, as it is hard to prevent oligos from getting degraded in lysosomes before they are translated. genentech paid them $310M upfront for a preclinical asset
Also correct about general delivery difficulties. Hadn't heard of Biontech's method - almost sounds like voodoo by your description.
I think there is interesting blocking and tackling happening on an organ-by-organ basis. E.g. GalNAc for liver hepatocytes, LNPs for systemic mRNA therapies, direct injection for eye or CNS (cheating, but still works). I'm partial to exosome hype...
Also no such discussion is complete without saying CRISPR, but the point remains that you can conjugate it targetted vehicles like antibodies. Conjugating to antibodies seemed to work for Stem :p
out of curiousity, what's the exosome hype? ive heard a few strong life sci VCs mention it, but i talked to a ceo of an exosome company and didnt quite understand the specific therapeutic potential
Happy to geek out more offline. Email in my profile.
id imagine the immunosuppressive dose would have to be pretty strong and come with a host of other risks. i know the immunosuppression load for gvhd is pretty heavy, and corticosteroids are not fun drugs
viruses are useful because they have evolved to insert foreign DNA into host cells. nothing humans can conceivably engineer has come close yet to the ability of viruses to do this
however viruses have also evolved a lot of bad qualities that cause disease. AAV is nice because 1) it is not known to cause disease, 2) only causes a mild immune response (so the body doesnt reject it before it does its work) and 3) is replication defective, so it wont reproduce uncontrollably in your body
all that said, viral vectors are far from perfect. the biggest issue is that you can usually only inject them once. after one injection, the immune system learns to recognize the virus as foreign, and upon subsequent administrations it will kill the virus before it can transfect cells. also, there is some risk that the viral genome can integrate with the host genome in ways that arent ideal.
from what i understand, the liver and the eye are really the only easily targeted specific tissues. the viruses are naturally carried to the liver, and the physiology of the eye enables viruses to get into cells there easily. getting viruses just to the brain, or heart, or pancreas, is much more challenging
aav technology has been around for a while, but there have been many false starts. back in the late 90s there were copmanies delivering genes into the brain with AAVs to treat parkinsons and alzheimers, and the genes got integrated and expressed by the right cells. however, the diseases were too complex for just one gene to cure them. in many ways, the advances in biology are enabling us to find what diseases are "right" for gene therapy, althoguh vector tech has improved as well