[fgimenez]

I sincerely think we are in the gene therapy renaissance. Delivery has always been an issue, but there are new tricks coming out with regard to cell-specific targeting. We can piggy back off the work done for RNA-based therapeutics (mRNA, ASOs, RNAi).

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.

[aaavl2821]

i agree, the hemophilia data looks really good, and avexis' spinal muscular atrophy product looks great as well. i dont know much about voyager but just looked at their press release for the study; looks like they are delivering a gene to increase dopamine production? do you know if this could be a disease altering therapy or just a "better" levodopa?

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

[fgimenez]

Yes, you could frame the Voyager treatment as "better levodopa". Though, the mechanism would feasibly mitigate neuro-degeneration and improve the terrible dose escalation of the drug.

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

[aaavl2821]

I dont understand the biology behind biontechs spleen targeting secret sauce (i dont think they did either, but it got them a patent on an otherwise standard lipid formulation). there is a really good nature paper from summer 2016 that outlines a lot of their preclinical dev; the CEO said he sort of regrets publishing that as a lot of competitors sprang up afterwards

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

[fgimenez]

They are a phenomenally cool drug delivery vehicle as you can get differential uptake based on their surface markers. Check this out: https://www.sciencedirect.com/science/article/pii/S221138351...

Happy to geek out more offline. Email in my profile.