CF is a progressive and life-threatening genetic disease caused by inherited mutations in the CFTR gene, which lead to insufficient CFTR function
The CFTR protein is found on epithelial cells throughout the body and is critical for proper salt and water balance in the cell, which drives production of freely flowing mucus for tissue hydration in the lungs, pancreas, and other organs. When the CFTR protein is not working properly, chloride—a component of salt—gets trapped in cells, causing thick mucus to accumulate in vital organs, leading to multisystem complications.
The ΔF508 mutation is considered a severe CF mutation, and individuals with this mutation tend to fall at the worst end of the CF severity spectrum because they have little or no CFTR function in epithelial cells. Approximately 90% of people with CF carry at least one copy of the ΔF508 mutation.
Optimal benefit to patients requires restoring normal CFTR function
While advances in the discovery and development of CFTR modulators have significantly improved the lives of people living with CF, at least two-thirds of patients on the current standard of care do not have normal CFTR function, defined as sweat chloride levels below 30 mmol/L. Patients with reduced CFTR function can experience debilitating multi-system complications that lead to significantly reduced quality of life and shorter life expectancy.
We believe stabilizing NBD1 is central to unlocking dramatic improvements in clinical outcomes and quality of life for CF patients. Despite having long been identified as a critical component for proper CFTR function, NBD1 has been considered “undruggable,” and none of the currently approved CF therapies directly stabilizes NBD1. Leveraging more than a decade of our co-founders’ research on NBD1, we are advancing a pipeline of small molecules engineered to correct the defects caused by the ΔF508 genetic mutation, which resides in the NBD1 domain.
Our approach: Stabilizing the unstable
The NBD1 domain of the CFTR protein plays a key role in the folding, stability and trafficking of CFTR to a cell’s surface, where it normally functions to conduct chloride and other ions and regulate the flow of water. The ΔF508 mutation severely destabilizes CFTR’s NBD1 domain, preventing normal folding and trafficking of CFTR to a cell’s surface and impairing chloride channel function.
We have employed biophysical, cell-based and virtual screening campaigns and extensive use of structural biology to guide the optimization of differentiated small molecule NBD1 stabilizers. Central to our development strategy is our use of the industry standard, clinically predictive preclinical cystic fibrosis human bronchial epithelial (“CFHBE”) model to measure CFTR function. We believe that the CFTR function improvement observed in our CFHBE model of our product candidates has the potential to translate clinically to deliver clinically meaningful benefit to CF patients.
Our vision is to build a CF franchise anchored by our NBD1 stabilizers to deliver clinically meaningful benefit to CF patients. We believe our robust pipeline of NBD1 stabilizers and complementary modulators provide multiple potential pathways to achieving that vision, either in combination with each other to produce a proprietary combination CF therapy, or in combination with the current standard of care.
We plan to evaluate multiple NBD1 stabilizer candidates and complementary modulator candidates and select the most potent and promising candidates to advance into later-stage development.
Our Scientific Presentations
Clinical Expert Videos
Guided by Clinical Experts in Cystic Fibrosis – Sionna Therapeutics sat down with members of its Clinical Advisory Board to hear their expert perspectives on the unmet needs in Cystic Fibrosis.
Supporting Scientific Literature
TOPIC:
CFHBE Assay
NBD1 / Biology
Unmet Need
NBD1 / Biology
Unmet Need
CFHBE Assay
Helpful resources
We encourage families to seek out resources from leading health organizations and the CF advocacy community.