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Updated: Oct 17, 2026
Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients
Published on: February 11, 2017
A phase 2a study with SPL84: A novel RNA-targeted approach to restore CFTR function in people with CF carrying the
Szczepan Cofta1, Daria Springer1, Kęstutis Malakauskas2
1Klinika Pulmonologii, Alergologii i Onkologii Pulmonologicznej, Uniwersytetu Medycznego im. KM, Poznan, Poland.
Background:
The 3849+10 kb C→T mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leads to aberrant splicing and the inclusion of a cryptic exon harboring a premature stop codon, resulting in the production of non-functional CFTR protein. SPL84 is an inhaled antisense oligonucleotide (ASO) designed to correct CFTR splicing and restore functional CFTR expression in people with CF (pwCF) carrying this mutation.
Methods:
This Phase 2a randomized, placebo-controlled, double-blind, multiple ascending dose study evaluated safety, tolerability, pharmacokinetics, and exploratory efficacy of inhaled SPL84 in pwCF carrying the 3849+10 kb C→T mutation. Participants received once-weekly inhalations of SPL84 (25 or 50 mg) or placebo for 9 weeks. Exploratory efficacy measures included changes in ppFEV1, ppFEF25-75, and CFQ-R respiratory symptom score.
Results:
Seventeen participants were included in the analysis, with fifteen completing all treatments. SPL84 was well tolerated with no drug-related serious adverse events. Most adverse events were mild or moderate and consistent with the underlying CF disease. Improvements in lung function, defined as change from baseline in ppFEV1≥5, were observed in up to 70% of the treated participants per cohort, accompanied by improvement of additional efficacy outcomes.
Conclusions:
Inhaled SPL84 demonstrated a favorable safety profile together with encouraging signals of clinical benefit in pwCF carrying the 3849+10 kb C→T mutation. These findings represent, to our knowledge, the first evidence of potential clinical benefit from a nucleic acid-based therapy targeting RNA in a pulmonary disease, supporting further evaluation of SPL84 as a mutation-specific, RNA-targeted treatment.
