Antisense oligonucleotides (ASOs) are a clinically validated class of medicines that selectively target RNA to modulate gene expression. Several ASO-based therapies are already approved for rare genetic diseases, demonstrating the potential of this technology to address unmet medical needs.

Recent advances in cystic fibrosis (CF) biology have shown that CFTR expression is regulated not only by gene mutations but also by RNA-level mechanisms, including mRNA stability and microRNA-mediated regulation. These discoveries open new therapeutic opportunities aimed at increasing CFTR expression upstream of the protein itself.

ACT-101 is a first-in-class RNA therapeutic based on a patented antisense oligonucleotide (ASO) targeting a novel post-transcriptional regulatory mechanism of the CFTR gene. Unlike current CFTR modulators and emerging therapeutic approaches, ACT-101 acts upstream by masking regulatory microRNA binding sites located within the 3’UTR of CFTR mRNA. This stabilization prevents CFTR mRNA degradation and durably restores endogenous CFTR protein expression without altering the gene sequence. This approach has the potential to address a broad range of CFTR mutations, including those currently ineligible for available therapies.

Preclinical studies performed using the gold-standard air-liquid interface (ALI) model of primary patient-derived bronchial epithelial cells demonstrated restoration of CFTR functional activity of up to 60% across several clinically relevant genotypes, including F508del homozygous and compound heterozygous, I507del, N1303K, and the nonsense mutation Y122X.

By leveraging advances in RNA biology and antisense technologies, ACT-101 has the potential to complement existing CFTR modulators and address the significant unmet needs of patients with incomplete or absent responses to current therapies.