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Thread: Kalydeco and Class IV Mutations

  1. #11
    Senior Member
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    May 2008
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    Kalydeco and Class IV Mutations

    This x 1000! I am hoping that a journal article will help people get the drug off-label.

  2. #12
    Junior Member
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    Mar 2012
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    7

    Kalydeco and Class IV Mutations

    @GenH- Thanks for the reply, Yes those are precisely what I was referring to. I had originally thought that one slide was a strong piece of evidence to get the rx, but it now might be the opposite. Especially given the registry data and the fact that there are twice as many known 347P's than 347H's, why would they include the H's over the P's unless there was little or no effect? I believe I understand the basic theory behind the mutation classes and how the drug works, but I am definitely not a biochemist, so who knows. I just know Van Goor has said himself that all CFTR, even wild type, are potentiated by Kalydeco. So, since class IV's make it to the cell membrane I assumed it would be effective. Maybe they all are but just not clinically substanitial?
    @kristen- This is definitely awesome news for the cf community. And hopefully after their trials this summer they can quickly open up use to more mutations!

  3. #13
    Senior Member
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    Dec 2008
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    Kalydeco and Class IV Mutations

    You never know unless you try.
    I never understand everyone saying "we don't think insurance won't cover it." OK. But have you TRIED? TRY!
    I battled the insurance because, well, I told my doc I would. He said my insurance wouldn't cover it.
    But they did.....because i TRIED!

  4. #14

    Kalydeco and Class IV Mutations

    Yes I see what you mean about including data about R347H but not R347P (given that there are more Ps). They did say they had genetic evidence for 55 mutations though, and they did not list 55, so there are some others. I found it interesting when I read in the slideshow that the normal CFTR channel can be potentiated by Kalydeco as well (doubled the probability of it being open), so yes I agree, if Kalydeco can still interact properly with the mutated CFTR channel that is on the surface, then it's likely there would be an increase in its function (could be anything from a small to large increase). The H and P amino acids are quite different, so even though the mutation is at the same spot Kalydeco may not potentiate it as well (the 3D structure of the channel would be different with the two amino acids, so Kalydeco may not interact in the same way).

  5. #15
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    Sep 2011
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    Kalydeco and Class IV Mutations

    I printed everything I could find on people taking it off label (Thanks to those for paving the way <img src="i/expressions/face-icon-small-smile.gif" border="0">) And I took him a huge stack of papers to back up why I believe my daughter should be allowed to try this life saving medication. I gave it to him Saturday and he has not got back with me yet. But I will definitely let everyone know when he does. <img src="i/expressions/face-icon-small-smile.gif" border="0"> Hopefully it will be good news, if not I will be asking for advice. <img src="i/expressions/face-icon-small-smile.gif" border="0">

  6. #16

    Kalydeco and Class IV Mutations

    HI,
    I think that currently they don't know if kalideco is useful for r347p, becouse it has not been tested. So, it could be!
    Also becouse all the other mutation of Class IV tested have shown (at least) same positive effects.
    I also know of on other patients (with r347p) waiting to start using kalydeco, off label.
    So, there is HOPE!
    Annalisa

  7. #17
    Junior Member
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    Apr 2012
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    6

    Kalydeco and Class IV Mutations

    Hi,
    Can someone explain the main difference in mutation regarding the last letter?
    What the latest letter means exactly?
    I've got almost the same question mark at my side. My son is G970D and it seems that G970R is in the list of potential candidates for VX770.
    How far are the mutations ?
    Thanks for your help


  8. #18
    DrRoe
    Guest

    Kalydeco and Class IV Mutations

    Here's some info from the abstract for Van Goore et al's study, I don't have access to this journal so if anyone else can post more info on this study I would love to read it.

    ==================================
    Ivacaftor potentiation of multiple CFTR channels with gating mutations

    Haihui Yu, Bill Burton, Chien-Jung Huang, Jennings Worley, Dong Cao, James P. Johnson Jr., Art Urrutia, John Joubran, Sheila Seepersaud, Katherine Sussky, Beth J. Hoffman, Fredrick Van Goore


    "Ivacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations."

    "Conclusion

    These in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D."

  9. #19

    Kalydeco and Class IV Mutations

    The CFTR chloride channel is a protein that is made up of amino acids. There are 1480 amino acids in a row that make up the CFTR channel. The number in the mutation is the position where the mutation is (eg G551D has a mutation at amino acid 551). The letters represent the amino acids. In this case the 'G' amino acid has been replaced by a 'D' which means the change of just one amino acid causes the mutation. In your sons case the amino acid at position 970 has been changed from a G to a D. If an amino acid is changed (from the normal protein) the 3D structure of the protein might be altered, and the channel may not work in the same way compared to normal. (This is a simplified explanation, the amino acid change may also change other properties of the channel eg whether it is postive/negative- this can affect how well it works as well)Two mutations which both have the same number (so the mutation is in the same spot) may have very different amino acids. This means the mutations can be quite different despite the fact they are in the same spot. This is a link with the amino acids and their letter 'codes' http://upload.wikimedia.org/wikipedi..._Acids.svgAlso the del or triangle in F508del means the 'F' amino acid is deleted at position 508.The X in G542X means the 'G' amino acid has been changed for a stop codon at position 542. This means the protein stops being made at that point (so a full length normal channel is not produced).There are also splicing mutations and frameshift mutations (more complex!).Kalydeco needs to interact with the CFTR channel in order for Kalydeco to improve the function of the channel. It is likely the 3D structure of the channel and the properties of the specific mutation determine how well they interact. Do you know what class G970D is?

  10. #20
    Senior Member
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    Dec 2008
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    Kalydeco and Class IV Mutations

    Great post.....thank you for this!

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