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  • thirdmeinvestor thirdmeinvestor May 13, 2012 8:45 PM Flag

    Hypothesis I: f508d defects vary & this explains great combo results

    Verity, I assume that the crux of the question you want to answer with your hypothesis I has to do with the diverse clinical response to VX-809.

    Accumulation of abnormal proteins can bring about a major toxic burden for the cell and even compromise the organism's viability. Hence, adaptation and survival have forced evolution to create ‘quality control’ mechanisms, called [conformational checkpoints], that detect, monitor, and degrade such abnormally folded gene products.

    Apparently, a majority of F508del mutant CFTR proteins is degraded even before reaching the cell membrane. This is a distinct property of 508 unlike that of 551. I would like to think that VX-809, sort of, mends the missing link at the phenylalanine at the 508th position, so that the checkpoint mechanisms find some of the repaired CFTR to have a close-to normal conformation ( = structure of protein folding). Then, some of VX-809 treated CFTR can survive degradation and would reach the cell membrane.

    Now, the central question you are asking is that why clinical phenotype is good for some but mediocre for others. It has been established that 508 mutant is unstable at the body temperature even if it survives degradation (it is stable at 25C). My hypothesis here is that 809 mended 508 CFTR assumes diverse conformation because of remaining instability of the conformation, some will have intact channel activity and others less without the help of Kalydeco(the missing phenylalanine resides near the interface of cell membrane and the cell interior). This explains why VX-661 and 809 may have positive clinical phenotype without Kalydeco. The diverse conformation for the mended CFTR proteins even with the presence of Kalydeco would make the overall phenotypes to be diverse.

    The above is my explanation as to why the same genotype does not lead to the same phenotype even with the help of the drugs.

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    • Third,

      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.

      Thoughts???

      • 1 Reply to verityvoila
      • 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.

 
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