choco_queen
New member
Hi, i'm new to the forum but I've been lurking for years. I am 35 with CF and I have an 8 year old boy. My health has been very slowly declining over the years, FEV1 never went over 40% after I had my son ( I was at 55% when became pregnant), I am currently sitting between 22%-32%. I have tried not to get my hopes up about any new drugs, I find it easier to cope with life that way. However, I now feel like time is running out and I guess I am starting to get desperate to find something to help me stay around for my little boy as long as possible.
I have tried to do some research about my mutations (d508 and E92K) and I have found some information on E92K and VX809 shown in the link below. The way I understand it, VX809 will correct E92K at high concentrations but when combined with d508, it somehow doesn't work. Have I understood that correctly?
I know that Orkambi is primarily for dd508, but given that VX809 does seem to have an effect on E92K do anyone think this may help people with my mutation too?
Thanks in advance
Link:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784376/
In particular:
VX-809 suppresses folding defects in CFTR caused by disease-related mutations in MSD1
Data presented thus far suggest that MSD1 is the minimum-length fragment required for VX-809 action. There are several CF-associated mutations in MSD1 that cause defects in CFTR processing and function: N-terminal tail (E56K and P67L), TM1 (E92K), TM2 (L206W), and TM4 (V232D) (Figure 4, A–E). The severe folding (Figure 4, A–B) and functional (Figure 4E) defects exhibited by E56L, P67L and L206W were completely corrected by 5 μM VX-809. In contrast, 5 μM VX-809 only partially restored folding and function to E92K and V232D (Figure 4, A and andE).E). Interestingly, VX-809 demonstrated reduced potency for E92K-CFTR relative to F508del-CFTR, for both correcting folding and function (Figure 4, B and andC),C), yet was able to fully restore E92K-CFTR at 30 μM. However, Corr4a could not restore E92K-CFTR function (Figure 4D).
FIGURE 4:
Functional defects in CFTR caused by disease-related mutations in MSD1 are suppressed by VX-809. (A) Folding defects caused by mutation of CFTR's N-terminus are differentially suppressed by VX-809 (5 μM). (B) Dose-dependent correction of E92K-CFTR ...
V232D-CFTR was the least responsive to VX-809, and higher concentrations of the compound did not restore function beyond the 25% of normal CFTR observed in the presence of 5 μM VX-809. Taken together with the observation that Corr4a restored V232D-CFTR biogenesis and function to normal levels (Caldwell et al., 2011
), these data suggest that correctors such as VX-809 and Corr4a can act to selectively suppress folding defects in CFTR caused by different disease-related mutations in MSD1.
Because E92K-CFTR was corrected to normal levels of function but F508del was corrected to ∼15% of normal function, the impact of VX-809 on the double mutation E92K/F508del-CFTR was tested. (Figure 4B). The effect of VX-809 on the C-band of E92K/F508del-CFTR was consistent with the dose response for E92K-CFTR, while the level of efficacy was consistent with that for F508del-CFTR. Thus the E92K mutation causes a folding defect in E92K/F508del-CFTR that requires a higher compound concentration, but the folding defects caused by F508del limit the efficacy of VX-809. These data support the concept that VX-809 action on MSD1 aids in suppression of some but not all of the folding defects caused by ΔF508.
VX-809 is highly efficacious at correction of folding defects in CFTR caused by some, but not all, of the missense mutations in MSD1 that were evaluated. E92K is unique among these mutants, as it alters the potency of VX-809, yet the biogenic defects caused by this mutation are completely corrected by VX-809. Mutational analysis of E92 suggested that mutation of this residue disrupts a salt bridge in MSD1 that is required for CFTR folding (Figure S3). E92 may therefore not be directly involved in binding VX-809 and instead appears to be required for folding of MSD1 to a conformation that binds VX-809 with high affinity.
I have tried to do some research about my mutations (d508 and E92K) and I have found some information on E92K and VX809 shown in the link below. The way I understand it, VX809 will correct E92K at high concentrations but when combined with d508, it somehow doesn't work. Have I understood that correctly?
I know that Orkambi is primarily for dd508, but given that VX809 does seem to have an effect on E92K do anyone think this may help people with my mutation too?
Thanks in advance
Link:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784376/
In particular:
VX-809 suppresses folding defects in CFTR caused by disease-related mutations in MSD1
Data presented thus far suggest that MSD1 is the minimum-length fragment required for VX-809 action. There are several CF-associated mutations in MSD1 that cause defects in CFTR processing and function: N-terminal tail (E56K and P67L), TM1 (E92K), TM2 (L206W), and TM4 (V232D) (Figure 4, A–E). The severe folding (Figure 4, A–B) and functional (Figure 4E) defects exhibited by E56L, P67L and L206W were completely corrected by 5 μM VX-809. In contrast, 5 μM VX-809 only partially restored folding and function to E92K and V232D (Figure 4, A and andE).E). Interestingly, VX-809 demonstrated reduced potency for E92K-CFTR relative to F508del-CFTR, for both correcting folding and function (Figure 4, B and andC),C), yet was able to fully restore E92K-CFTR at 30 μM. However, Corr4a could not restore E92K-CFTR function (Figure 4D).
FIGURE 4:Functional defects in CFTR caused by disease-related mutations in MSD1 are suppressed by VX-809. (A) Folding defects caused by mutation of CFTR's N-terminus are differentially suppressed by VX-809 (5 μM). (B) Dose-dependent correction of E92K-CFTR ...
V232D-CFTR was the least responsive to VX-809, and higher concentrations of the compound did not restore function beyond the 25% of normal CFTR observed in the presence of 5 μM VX-809. Taken together with the observation that Corr4a restored V232D-CFTR biogenesis and function to normal levels (Caldwell et al., 2011
Because E92K-CFTR was corrected to normal levels of function but F508del was corrected to ∼15% of normal function, the impact of VX-809 on the double mutation E92K/F508del-CFTR was tested. (Figure 4B). The effect of VX-809 on the C-band of E92K/F508del-CFTR was consistent with the dose response for E92K-CFTR, while the level of efficacy was consistent with that for F508del-CFTR. Thus the E92K mutation causes a folding defect in E92K/F508del-CFTR that requires a higher compound concentration, but the folding defects caused by F508del limit the efficacy of VX-809. These data support the concept that VX-809 action on MSD1 aids in suppression of some but not all of the folding defects caused by ΔF508.
VX-809 is highly efficacious at correction of folding defects in CFTR caused by some, but not all, of the missense mutations in MSD1 that were evaluated. E92K is unique among these mutants, as it alters the potency of VX-809, yet the biogenic defects caused by this mutation are completely corrected by VX-809. Mutational analysis of E92 suggested that mutation of this residue disrupts a salt bridge in MSD1 that is required for CFTR folding (Figure S3). E92 may therefore not be directly involved in binding VX-809 and instead appears to be required for folding of MSD1 to a conformation that binds VX-809 with high affinity.