Cystic fibrosis (CF) is a serious, potentially fatal inherited disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an ion channel protein that helps regulate the flow of chloride ions and water in and out of epithelial cells lining the lungs, pancreas and other organs. These CFTR mutations prevent the protein from functioning normally and ultimately lead to a buildup of mucus in the lungs and airways, impaired pancreatic secretion and other aspects of CF pathology that compromise patient health. Correction of the defective NBD1 domain of CFTR has the potential to deliver greater efficacy than current therapies and provide a potential solution for the functional defects at the core of CF.
Optimal benefit to patients requires restoring normal CFTR function
The past three decades have witnessed great progress for patients with CF, but there’s still a significant need to provide better therapeutic options for this debilitating genetic disease that affects more than 100,000 people globally.
Current CFTR modulator therapies for people with CF are designed to increase CFTR function by either increasing the quantity of CFTR protein at the cell surface or by helping CFTR channels to open and allow chloride ions to cross the cell membrane. While these therapies can improve CFTR function, in most people with CF they do so only partially. Most CF patients harbor a mutant form of CFTR known as ΔF508-CFTR. The ΔF508 mutation resides within the NBD1 domain of CFTR and severely destabilizes CFTR, preventing its normal trafficking to the cell surface and function. The inherent instability of ΔF508-CFTR and many other similar mutations is not fully corrected by current therapies and, as a result, many CF patients may still experience the ongoing effects of reduced CFTR function over time. This is in part because the field has not found a way to address defective NBD1 – until now.
At Sionna, our focus is on restoring normal CFTR function by fully stabilizing the structure of the CFTR protein in order to maximize patient benefit and sustain health for the long-term.
Our approach: Stabilizing the unstable
The ΔF508 mutation destabilizes CFTR’s NBD1 domain and leads to dysfunction and disease
The NBD1 domain of the CFTR protein plays a key role in the folding, stability and trafficking of CFTR to the cell surface, where it normally functions to conduct chloride and other ions and regulate the flow of water.
The most common CFTR mutation, called ΔF508, severely disrupts this protein, from the moment it is newly synthesized on the ER membrane, leading to a buildup of mucus in the lung and other organs and dysregulation throughout the body.
With the goal of fully normalizing CFTR function, we are creating therapies that stabilize NBD1, the key mechanism that current CF modulator therapies lack
We are creating small molecule therapies designed to restore CFTR function by stabilizing NBD1 – an approach that anchors all of our development strategies. Using established, clinically predictive CF models, our small molecules have shown remarkable effectiveness in vitro in normalizing folding, maturation and stability of the ΔF508-CFTR protein and allowing it to traffic properly to the cell surface where it’s needed to regulate the flow of ions and water.
Our mission is to restore optimal health for CF patients
Ultimately, we seek to restore the normal flow of chloride ions and water across epithelial membranes in people with ΔF508 and similar mutations, to provide these patients with normal CFTR function and preserved health.
We are advancing our lead candidates into IND-enabling studies as we continue to strive toward our mission of bringing fully normal health to CF patients.
We encourage families to seek out resources from leading health organizations and the CF advocacy community.