WS13.02Two children homozygous for the complex allele p.Leu467Phe-p.Phe508del with reduced clinical response to elexacaftor/tezacaftor/ivacaftor but differences in nasal potential difference measurement

Objectives

In vitro studies demonstrate that homozygosity for the complex allele p.Leu467Phe-p.Phe508del (L467F-F508del) is associated with failure to respond to Elexacaftor/Tezacaftor/Ivacaftor (ETI). The functional CFTR response in vivo in homozygous carriers of these mutations has not yet been investigated. We report clinical and functional responses towards ETI of two L467F-F508del homozygous children.

Methods

Both received functional assessments of CFTR responses via sweat chloride and nasal potential difference (nPD) measurements along with in vitro testing of responsiveness in primary nasal epithelial cell cultures before and during ETI and one child additionally during lumacaftor/ivacaftor (LUM/IVA) therapy.

Results

The diagnosis of CF was made in the 1st and 3rd year of life revealing F508del homozygosity in both cases. After initiation of LUM/IVA, no drop in sweat chloride was observed in either child. The girl was switched to ETI at the age of 11, and the boy at age 6 years. Lack of pronounced drop in sweat chloride after initiation of ETI in both children (- 18mmol/l to 85mmol/l and -15 mmol/l to 93 mmol/l, respectively) led to resequencing of CFTR, which revealed L467F homozygosity in both children. Both showed sub-par clinical responses with the girl experiencing continued decline in lung function and the boy demonstrating an above average number of pulmonary exacerbations. Both children received nPD measurements with and without ETI therapy, which showed discrepant responses. Whereas the boy did not have any activity-differences by nPD, the girl showed a sub-par, but notable response during ETI therapy. In vitro testing in nasal epithelial cell culture is pending.

Conclusion

The presence of L467F-F508del homozygosity does not lead uniformly abrogate CFTR's response towards modulation via ETI, but is associated with a significantly reduced response. Therefore further investigation of complex alleles on CFTR modulator responsiveness is important.