N1303K (p.Asn1303Lys) variant: Expanding frontiers in the treatment of cystic fibrosis.

Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by variants in both copies of the CF transmembrane conductance regulator (CFTR) gene, with F508del (p.Phe508del) being the most common variant. While CFTR modulators have revolutionized treatment, their efficacy is mutation-specific, leaving patients with rare variants like N1303K without approved therapeutic options. We present the case of a 21-year-old female with severe CF due to homozygosity for the N1303K variant. Faced with rapid clinical decline and ineligibility for approved therapies, a forskolin-induced swelling assay (FIS) on her intestinal organoids demonstrated a significant response to the triple CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI). Off-label ETI was initiated, resulting in improved pulmonary function, reduced exacerbations, and better quality of life. Despite initial progress with ETI, the patient experienced three hospitalizations over five months due to severe exacerbations, during which Burkholderia cepacia complex was identified for the first time, while the pre-existing chronic infection with Candida parapsilosis persisted. These infections were managed with personalized antimicrobial strategies, including inhaled meropenem and inhaled amphotericin, alongside ETI, leading to sustained clinical stability during an 8-month follow-up. This case highlights the potential of organoid-based testing to guide personalized CFTR modulator therapy for rare variants and underscores the importance of individualized antimicrobial strategies in addressing the complexities of CF. Expanding regulatory approval for modulators like ETI to include rare variants is essential for equitable CF care.