TABLE 1.
Predicted readthrough response to gentamicin and preclinical studies performed on cystic fibrosis patients carrying premature termination codons (PTCs)
| Mutation | In vitro assay | Preclinical studies | ||||||
|
Readthrough gentamicin# |
Target mRNA (exon skipping)# | Function# | Overall response¶ | Additional CFTR-directed treatments |
Readthrough gentamicin+ |
Readthrough PTC124+ |
Response | |
| p.Glu60* | Low | Low | Low | Low | Potentiator +corrector |
0/1 [21] | 0/1 (0%) | |
| p.Tyr122* | High | High | High | High | Potentiator | 6/9 [5] | 8/14 [19] | 14/23 (60%) |
| p.Ser434* | Moderate | High | High | Moderate | Potentiator | |||
| p.Ser466*UGA | High | High | Low | Low | Potentiator +corrector |
|||
| p.Gly542* | Moderate | High | Moderate | Moderate | Potentiator +corrector |
0/1 [5] 0/4 [21] 0/3 [20] |
4/4 [22] 2/3 [18] 8/14 [19] |
14/29 (48%) |
| p.Arg553* | Low | Low | Moderate | Low | Potentiator +corrector |
0/1 [5] 0/3 [21] 0/1 [20] |
1/2 [19] | 1/7 (14%) |
| p.Arg785* | Low | Low | High | Low | Potentiator | |||
| p.Trp846*UGA | High | Low | High | Low | Potentiator | 0/1 [19] | 0/1 (0%) | |
| p.Tyr1092*UAG | Low | High | Moderate | Low | Potentiator | 0/1 [21] | 0/1 (0%) | |
| p.Glu1104* | Low | High | Moderate | Low | Potentiator +corrector |
1/2 [19] | 1/2 (50%) | |
| p.Arg1128* | Moderate | High | High | Moderate | Potentiator | |||
| p.Arg1162* | Low | High | High | Low | Potentiator | 0/1 [5] 0/1 [21] |
1/2 [19] | 1/4 (25%) |
| p.Ser1196* | High | High | High | High | Potentiator | |||
| p.Trp1282* | Moderate | High | High | Moderate | Potentiator | 4/6 [23] 7/9 [13] 0/1 [5] 0/1 [21] 0/1 [20] |
12/17 [22] 8/14 [18] 2/4 [19] |
33/53 (62%) |
| p.Gln1313* | Low | High | High | Low | Potentiator | 0/1 [19] | 0/1 (0%) | |
CFTR: cystic fibrosis transmembrane conductance regulator. #: skill levels were assigned for the level of readthrough, the occurrence of exon skipping and the function of the major recoded channel, in order to assess overall treatment response (low, moderate or high). ¶: overall response was considered as low when at least one skill was low, moderate when at least one was moderate and the other(s) high, and high when all three skills were high. +: data are presented as numbers of responder/total patients for gentamicin or PTC124 [ref.]; patients carrying two different PTCs were not taken into account.