Hypothesis I: f508d defects vary & this explains great combo results
Thank you so much for your insights and for so kindly taking the time to explain this all to me–I really wouldn’t be able to understand much of this without your kind teaching.
You actually made me think more about “what” was the underlying crux of this hypothesis, and I think there are 3 things I’m trying to get at: 1) As you note, why are there diverse clinical responses?; but also 2) when we say “why” were there diverse clinical responses, not such the mechanism, but the underlying reason for the mechanism that caused the diverse responses and then what can be done to improve those responses; and 3) why were some of those responses so strong–stronger than in vitro suggested and Vertex expected.
Initially, I am struggling with a few things to understand your explanation. I completely understand what you are saying about the adaptation and survival/confromational checkpoint. (That helps so much b/c I didn’t quite get the misfolding thing but now I do!) But I’m struggling though with understanding how the channel activity relates this. Is the channel activity a second “checkpoint” to prevent defective protein from moving once at the cell surface, similar to the degradation response that prevents the misfolded protein from moving to the cell surface in the first instance? So with 551, the protein isn’t misfolded so it makes it past the first “checkpoint” but it is still defective, so it is not allowed to “channel?” I guess I’m wondering if there is a second thing that I’m missing here related to the channeling? Knowing this will help me understand your explanation and also to think through more why some response to 809 alone but not Kalydeco.
But if I am understanding what you wrote, then: 1) The reason for the diverse clinical response is that everyone’s body has a different survival checkpoint, i.e., “close enough” to “conformation” for one person is not good enough for another? (To use the “clubbing analogy”–different bouncers have different standards for “hot chicks?”) And relatedly, some of those “close enough” to “conformation” are seen by some Cfers’ bodies as “close enough” to channel freely; and thus no need for Kalydeco. Also, even some of those “close enough” proteins will later be rendered “rejects” because of further degradation, which also can vary be person. Is this right???
2) So then the second question is “why” is “close enough” okay for some and not others? I don’t understand evolutionary science much, but is merely part of that science that different bodies have higher/lower standards for “defective” genes, etc.? But I also wonder if there are other things that could affect. For instance, you mention body temp as causing the degrading: Could having a higher basal body temp/lower temp (hypothyroidism or is it hyper?) matter. My basal temp is 1 degree lower than the “norm” (thyroid issues)–so could things like that affect degradation? If that is the case, then maybe there is a way to “improve” 809's impact by either making more proteins look close enough (or prevent them from degrading) or altering how the body sees “close enough.” (Again, clubbing analogy–if you put a lot of make-up on, some might make it past the first “hot chick” checkpoint, or give enough beers to the bouncer.)
3) Finally, why were some of the results much better than I think Vertex expected–10% is basically Kalydeco and I believe Vertex said in vitro Kalydeco had fixed 50% of proteins while 809 only 30%. I wonder if it is either/both because: a) in vitro they were looking for “perfect” proteins, while the body only needed “close enough” and b) improved transcomplementation between the now-improved proteins.
A checkpoint mechanism itself is regulated by other gene products (proteins) and the degradation trigger threshold would depends on individual's regulatory genes. (This also contributes to the reason why phenotypes can differ when genotype is the same.) The drugs such as VX-809 effectively shift the degradation threshold to a higher level, the repaired CFTR is more stable and survive degradation. As you pointed out individual variation in drug response can come from the threshold difference.
By conformational instability I mean the changes (or jumping) of protein folding from one structure to another. Some conformation would more likely trigger degradation checkpoint than others.
Then a better drug would mean a drug that can stabilize the conformation around an optimal form so that a majority of them would survive to reach the cell surface.
Thanks. I think I follow, although lack of basic science formation is now making it more of a struggle because I don't really understand what other proteins/gene products would be. But I follow the explanation of what happens/why and why it differs by person so that helps a ton for me to just understand the info coming out of the studies. Thanks again for taking the time.
Any thoughts on my suggestion that 661 Phase 2a might be even better than 809 Phase 2b and jump right to Phase 3???