Table 1 A series of CFTR variants tested in the FRT model

From: A novel drug series optimized to address cystic fibrosis and other CFTR deficiency diseases of human airways

 

10 µM Forskolin

25 nM Forskolin

 

DMSO

DMSO

VX-661 + VX-445 + VX-770

   

+HDCF104

 

+HDCF104

Wildtype

100.0%

100.0%

   

F508del

 

2.4%

4.1%

32.0%

105.4%**

I507del

0.0%

0.0%

0.0%

0.0%

0.0%

R334W

7.3%

7.9%

6.3%

5.9%

8.9%**

R560T

0.0%

0.0%

0.4%

1.1%

1.2%

R1066C

0.1%

0.0%

0.0%

0.7%

1.2%*

V520F

0.4%

0.3%

0.4%

10.5%

20.6%*

A559T

0.0%

0.0%

0.0%

0.1%

0.3%

Y569D

0.0%

0.1%

0.3%

0.2%

0.7%

L1065P

0.2%

0.1%

1.0%

34.2%

57.8%*

L467P

0.6%

1.8%

2.0%

1.8%

2.1%

L558S

0.4%

1.8%

4.5%

5.4%

12.0%*

I1234V

2.8%

2.9%

6.6%

7.4%

11.5%*

L927P

12.0%

1.1%

8.8%

5.2%

21.1%**

L227R

0.1%

0.9%

3.6%

0.4%

4.7%*

Q359K/T360K

13.9%

0.8%

4.7%

5.9%

38.1%*

A561E

0.6%

0.6%

1.5%

3.4%

8.4%**

R560K

0.0%

0.0%

0.0%

1.9%

0.0%

W1098R

0.4%

0.5%

0.9%

1.1%

2.5%*

W57G

0.5%

0.5%

1.1%

1.0%

1.2%

H609R

2.6%

0.0%

8.0%

18.4%

53.8%**

P99L

1.3%

5.0%

18.6%

18.6%

45.8%*

D513G

2.2%

2.8%

7.8%

30.8%

64.2%**

Y563D

0.0%

0.0%

0.0%

0.1%

0.0%

S1118F

3.8%

1.7%

7.2%

6.8%

23.1%**

R560S

0.3%

0.0%

0.5%

0.8%

1.7%*

A613T

3.2%

2.2%

6.2%

21.4%

26.5%

G91R

1.1%

1.8%

0.3%

20.2%

37.5%*

L102R

0.1%

0.2%

0.9%

17.5%

18.6%

M1101R

0.0%

0.0%

0.8%

0.5%

1.1%

  1. Percent of wildtype CFTR activity in the presence or absence of ETI (24 h with VX-661 and VX-445, followed by acute addition of VX-770 during Ussing chamber measurements +/- HDCF104 are shown). Lines in bold font indicate activation of mutant CFTR beyond a 10% threshold of wildtype function often used in the FRT model to predict clinical benefit. Note: These experiments utilized a much lower forskolin concentration (25 nM) than the pharmacologic levels (5−10 µM) commonly used for testing new modulator compounds16,17,21,37,89. Stimulation of CFTR in FRT cells using nominal forskolin represents a stringent model for evaluating drug activation of mutant CFTR.
  2. *p < 0.05; **p < 0.005 for HDCF104 stimulation following ETI versus vehicle; n = 3–4 biologic replicates per condition; statistics were by t-test.
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