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Thread: Article: Fix two defects to combat cystic fibrosis

  1. #1
    cfsucks
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    Article: Fix two defects to combat cystic fibrosis

    [quote]
    <h3 class="updated published" title="20120312">Mar. 12, 2012</h3>
    <em>New research could provide roadmap for more effective drug discovery for CF</em>
    A recent study led by Gergely Lukacs, a professor at McGill University's Faculty of Medicine, Department of Physiology, and published in the January issue of <em>Cell,</em> has shown that restoring normal function to the mutant gene product responsible for cystic fibrosis (CF) requires correcting two distinct structural defects. This finding could point to more effective therapeutic strategies for CF in the future.
    CF, a fatal genetic disease that affects about 60,000 people worldwide, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein involved in ion and water transport across the cell surface. As such, CF is characterized by impaired chloride secretion causing the accumulation of viscous mucous that may cause multiple organ dysfunctions, including recurrent lung infection.
    The most common mutation in CFTR, known as deltaF508, is caused by a single amino acid deletion and results in a misfolded version of CFTR that is retained within the cell and quickly degrades rather than being trafficked to the cell membrane where it would function as a chloride channel.
    In 2005, Lukacs and his lab suggested that deltaF508 mutation effect is not restricted to the domain (the nucleotide binding domain 1 or NBD1, one of five building blocks of CFTR) where the deltaF508 is located. Specifically, his team found that the mutation destabilizes the NBD1 as well as the NBD2 architecture, suggesting that domain-domain interaction plays a critical role in both normal and pathological CFTR folding.
    Building on his team's previous work and computer generated models of CFTR, Lukacs and his team set out to determine whether it was possible to correct both NBD1 stability and domain-domain interaction defect. Using a combination of biophysical, biochemical and genetic techniques, the team found that only simultaneous correction of both folding defects was able to ensure normal-like cell surface expression and function of the mutant.
    "These findings offer a plausible explanation for the limited efficiency of the available correctors currently under clinical trial. If there are two different folding steps to correct, it is difficult to envision how a single drug could work," explained Lukacs. "The proposed two-step folding model points to the fact that the correction strategy has to be reconsidered."
    The study was funded in part by The Cystic Fibrosis Foundation, Cystic Fibrosis Canada, The Canadian Institutes for Health Research (CIHR), Canada Research Chair (CRC) program and the Canada Foundation for Innovation (CFI).


    </blockquote>
    <strong>Is this bad news for the vertex drugs and DF508? or is this what they are addressing by using VX-809/661 in combination with Kalydeco?</strong>

    Here's the study link:
    http://www.cell.com/abstract/S0092-8674%2811%2901368-7

  2. #2
    cfsucks
    Guest

    Article: Fix two defects to combat cystic fibrosis

    [quote]
    <h3 class="updated published" title="20120312">Mar. 12, 2012</h3>
    <em>New research could provide roadmap for more effective drug discovery for CF</em>
    A recent study led by Gergely Lukacs, a professor at McGill University's Faculty of Medicine, Department of Physiology, and published in the January issue of <em>Cell,</em> has shown that restoring normal function to the mutant gene product responsible for cystic fibrosis (CF) requires correcting two distinct structural defects. This finding could point to more effective therapeutic strategies for CF in the future.
    CF, a fatal genetic disease that affects about 60,000 people worldwide, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane protein involved in ion and water transport across the cell surface. As such, CF is characterized by impaired chloride secretion causing the accumulation of viscous mucous that may cause multiple organ dysfunctions, including recurrent lung infection.
    The most common mutation in CFTR, known as deltaF508, is caused by a single amino acid deletion and results in a misfolded version of CFTR that is retained within the cell and quickly degrades rather than being trafficked to the cell membrane where it would function as a chloride channel.
    In 2005, Lukacs and his lab suggested that deltaF508 mutation effect is not restricted to the domain (the nucleotide binding domain 1 or NBD1, one of five building blocks of CFTR) where the deltaF508 is located. Specifically, his team found that the mutation destabilizes the NBD1 as well as the NBD2 architecture, suggesting that domain-domain interaction plays a critical role in both normal and pathological CFTR folding.
    Building on his team's previous work and computer generated models of CFTR, Lukacs and his team set out to determine whether it was possible to correct both NBD1 stability and domain-domain interaction defect. Using a combination of biophysical, biochemical and genetic techniques, the team found that only simultaneous correction of both folding defects was able to ensure normal-like cell surface expression and function of the mutant.
    "These findings offer a plausible explanation for the limited efficiency of the available correctors currently under clinical trial. If there are two different folding steps to correct, it is difficult to envision how a single drug could work," explained Lukacs. "The proposed two-step folding model points to the fact that the correction strategy has to be reconsidered."
    The study was funded in part by The Cystic Fibrosis Foundation, Cystic Fibrosis Canada, The Canadian Institutes for Health Research (CIHR), Canada Research Chair (CRC) program and the Canada Foundation for Innovation (CFI).


    </blockquote>
    <strong>Is this bad news for the vertex drugs and DF508? or is this what they are addressing by using VX-809/661 in combination with Kalydeco?</strong>

    Here's the study link:
    http://www.cell.com/abstract/S0092-8674%2811%2901368-7

  3. #3
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    Article: Fix two defects to combat cystic fibrosis

    This is why our doctor was saying that DF508 and other similar mutations may need all 3 of the vertex drugs. Two to properly fold the protein and one to get it through the gate.

  4. #4
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    Article: Fix two defects to combat cystic fibrosis

    This is why our doctor was saying that DF508 and other similar mutations may need all 3 of the vertex drugs. Two to properly fold the protein and one to get it through the gate.

  5. #5
    cfsucks
    Guest

    Article: Fix two defects to combat cystic fibrosis

    That's what I thought until I read that vx-809 and 661 are the same thing- they are just metabolized differently in the body- or combined do they correct both these issues in the df508 gene that the author found?

  6. #6
    cfsucks
    Guest

    Article: Fix two defects to combat cystic fibrosis

    That's what I thought until I read that vx-809 and 661 are the same thing- they are just metabolized differently in the body- or combined do they correct both these issues in the df508 gene that the author found?

  7. #7
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    Article: Fix two defects to combat cystic fibrosis

    I don't know. Hopefully a clinical trial to confirm this theory will emerge soon.

  8. #8
    Senior Member
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    Article: Fix two defects to combat cystic fibrosis

    I don't know. Hopefully a clinical trial to confirm this theory will emerge soon.

  9. #9
    cfsucks
    Guest

    Article: Fix two defects to combat cystic fibrosis

    anyone else have any insight into this?

  10. #10
    cfsucks
    Guest

    Article: Fix two defects to combat cystic fibrosis

    anyone else have any insight into this?

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