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VX770 and R347P

Question
Dear Team, I refer to the question you have already (partly) answered before. I think the more concrete questions is: if VX770 will help R117H - how likely is it that it can work on R347P (or any other class 4 mutation which is not a gating/class 3 mutation)? It is difficult to understand the differences in the mutations themselves. I thouhgt that R117H has a gating defect as well as G551D (reduced channel open time), and R347P has a conductance problem. Thank you very much for you answer.
Answer
Dear Questioner

Thank you for your question, hopefully I can provide the information to further clarify your question.

KALYDECO (VX-770) helps CFTR protein function more normally once it reaches the cell surface.
Therefore it could potentially help mutations where the CFTR protein is produced and reaches the cell surface; but does not open regularly or does not open at all.

In gating mutations like G551D (class III mutation), the defective protein in CF moves to its proper place at the cell surface but does not function correctly. The CFTR protein instead acts like a locked gate, preventing the proper flow of salt and fluid in and out of the cell. Kalydeco aims to unlock that gate.

The R117H mutation (class IV mutation) known as a conductance mutation, causes abnormal function of the CFTR protein at the cell surface. Research has shown that with this mutation, CFTR can retain the ability to conduct chloride. Therefore it is possible that this mutation will be associated with a partial or variable CF phenotype. This research is currently under peer review, and specific experimental details will be available once that has concluded.
In a R347P Mutation (class IV mutation) causes a similar problem. THE CFTR protein does not mature normally and/or does not conduct enough chloride to be functional at the cell surface. This is consistent with a disease-causing mutation. This research is currently under peer review and specific experimental details will be available once that activity has concluded.
The recent clinical trials of KALYDECO in patients with a G551D mutation, found the drug to be safe and effective. The mechanism of KALYDECO and the results from the trials in people with a G551D mutation suggest that this drug could also work in the same way in people with other class IV mutations. However more research is needed to fully answer this question.
Future Vertex programmes to study the effects of KALYDECO in people with the R117H mutation are currently being set up as this is the next most common class IV mutation in people with CF worldwide. There are plans to extend this research into other gating mutations, possibly to include the R347P mutation (which account for a smaller % of class IV mutations).
It is hoped that KALYDECO will work in these mutations however, as these are very new therapies, before these trials have been carried out, it is difficult to predict exactly how effective the drug will be in people with R117H or R347P mutations due to the differences between the mutations as outlined above.
Clinical trials are essential to establish that the drug is safe and effective before it can be indicated for use.
References
Elborn JS. Fixing cystic fibrosis CFTR with correctors and potentiators. Off to a good start. Thorax 2012 January 01;67(1):4-5.
Sheppard, D.N., Rich, D.P., Ostedgaard, L.S., Gregory, R.J., Smith, A.E. & Welsh, M.J. 1993, "Mutations in CFTR associated with mild-disease-form CI- channels with altered pore properties", Nature, vol. 362, no. 6416, pp. 160-164
www.cftr2.org/

Vertex Pharmaceuticals Incorporated Press release January 8, 2012 Vertex Announces Key 2012 Business Objectives as Company Prepares for Planned Global Launch of KALYDECO in Cystic Fibrosis
Vertex Pharmaceuticals Incorporated Press release January 31, 2012 FDA Approves KALYDECOâ„¢ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis

Best wishes
Katherine ONeill
Stuart Elborn

03.07.2012
The answer is edited by: Prof Stuart Elborn