eventually getting tissue-specific delivery could result in tx for tough diseases like IPF where there is no 'master fibrosis enzyme'. you have a huge ensemble to adjust: think like a music producer smoothly adjusting several EQ bands vs. the drug which annihilates one band

personally i think there are too few liver diseases left to battle with nucleic acids (ask NTLA), drugging ALD would be a huge win, no doubt a 2B+ drug, but PK/exposure here may be tricky. if you drug with a mRNA encoding the TF you might have a better chance

don't forget immunogenicity. controlling PK/PD here seems very hard. still exciting new idea and those don't come up very often in biopharma. Sangamo and a few others once got around this hoop but never exactly on the TF-or-bust wavelength

@MartinShkreli So many complexities and unknowns complicate scaling TF tx-- though, two additional subtle advantages here are that TFs are smaller than gene therapy machinery and TF activity is more impacted by cell context, which could be leveraged to restrict tx effects to target cell types.

@bffswithbiology well gene therapy (vectors) dont even go the machinery route -- concatemeric episomes!

@MartinShkreli ALD will be treated via engineered microbes

@MartinShkreli

@MartinShkreli Machinery, as in anything expressed from vectors. In the case of d/Cas9 expression, which is a large ORF, one could replace that with >=2 TFs or other therapy modifiers. Payload length is a major constraint for AAV delivery.

@MartinShkreli Does this come to data on which diseases have small TF induced disruptions? i.e. do we know enough about IPF to perturb the environment to have certainty the drug will work.

@plainyogurt21 i think TFs can certainly help dial in the orchestra of changes needed in some illnesses. how about something like autoimmunity where we pretend one pathway rules it all: TNF, etc.

steroids of course work through transcription factors!

@MartinShkreli P.s. great analogy - that is how cell state reprogramming and partial cellular reprogramming looks.

@MartinShkreli It is possible to find master controllers of lung fibrosis though, as we have done . . .

@MartinShkreli If only someone would devote their time to solving the hard problem in RNA medicine and get us out of our liver limitation. A boy can dream ;)

@MartinShkreli you dont even believe pizzagate is real so hard to believe anything you say these days. cant even say water is wet.

@bffswithbiology i guess its a bit fungible if you're using mRNA. really only two pathways to expression

TFs have that pleiotropy that is hard to account for

@MartinShkreli AAV delivery with epicrispr for FSHD

@MartinShkreli lots of focus on tissue here, but designer TFs for living cell therapeutics is also a valuable pursuit

@MartinShkreli or PAMs of acetylcholine receptors, or cd130 agonists