Cystic fibrosis is a debilitating and devastating respiratory disease
In May, cystic fibrosis awareness month, we aim to highlight some of the pioneering work on this often debilitating and devastating respiratory disease.
Advancing therapies for rare CFTR mutations in cystic fibrosis
Cystic fibrosis (CF) is a life-shortening, recessive disorder caused by mutations in the CFTR chloride channel, leading to thickened airway secretions and chronic respiratory infections. While CFTR-targeting drugs such as ivacaftor and the elexacaftor-tezacaftor-ivacaftor combination have revolutionized care for many patients, they do not correct the defects in all rare CFTR variants.
Evidence-based medicine is transforming CF treatment
At the University of Bristol, Prof. David Sheppard’s lab has been at the vanguard of CFTR biophysics. In a study led by Dr. Hongyu Li, single-channel recordings revealed that two rare CFTR mutants (S1159F and S1159P) exhibit drastically reduced open probability and are poorly responsive to ivacaftor (and even triple-combination therapies). These findings not only explain why carriers of these mutations fail to benefit from existing modulators but also establish a sensitive in vitro assay platform for screening novel potentiators tailored to these refractory channels.
"Evidence-based medicine has led to progressive improvements in the health of people with cystic fibrosis, while elexacaftor-tezacaftor-ivacaftor has transformed the outlook for many, but not all people with cystic fibrosis. This incentivises the cystic fibrosis community to do more, quicker to bring life-changing therapies to all people with cystic fibrosis. I am especially grateful to my colleagues past and present for their commitment and dedication to cystic fibrosis research and the Cystic Fibrosis Trust for funding our work"
Targeting TMEM16A with automated patch clamp to fast track CF therapies
Meanwhile, Enterprise Therapeutics has pursued a complementary approach by targeting TMEM16A, a “bypass” chloride channel that can substitute for defective CFTR. Under the leadership of CSO Dr. Martin Gosling, and in collaboration with Sophion Bioscience, they deployed a high-throughput FLIPR-Automated Patch Clamp workflow on the QPatch platform to screen over 20,000 compounds in just two weeks. This effort yielded potent TMEM16A enhancers that can restore chloride flux independently of CFTR genotype – a programme later acquired by Roche-Genentech in October 2020.
"We are incredibly grateful for the support Sophion has provided to us and the programme. Automated electrophysiology has been KEY not only in finding the chemistry start points but in supporting the programme through its entire lead optimisation. The QPatch has been the primary assay and in our hands provides robust, reliable data with an exceptional correlation to the data from ion transport for TMEM16A"
Taken together, these parallel academic and biotech endeavours exemplify the twofold strategy now emerging in CF drug discovery: precision correction of individual CFTR mutants where possible, and activation of alternative ion channels to bypass intractable defects. As Prof. Sheppard reflected on six decades of Cystic Fibrosis Trust funded research, and Enterprise Therapeutics readies its TMEM16A potentiators for clinical development, the field moves steadily toward life-changing therapies for all people with CF.
Read Li, Sheppard et al. here
Read a review of CF, CFTR, TMEM16A and the Enterprise Therapeutics/Sophion collaboration, see the whitepaper written by Drs. Martin Gosling, Sarah Lilley and Sophion here
Dr. Henry Danahay (Head of Biology, Enterprise Therapeutics) will be presenting their latest research at Sophion’s ICMS in Cambridge. Sign-up here