BACKGROUND
Cystic Fibrosis (CF) is a chronic multi-organ disease that affects between 70,000 - 100,000 people worldwide. The symptoms of the disease include chronic respiratory infections, pancreatic insufficiency, and gastrointestinal disease. The disease is caused by loss-of-function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR) which is an ABC transporter-class ion channel protein that conducts chloride ions across epithelial cell membranes in vertebrates. This loss-of- function presents significant morbidity for individuals with CF.
Health outcomes markedly improved with arrival of CFTR modulators – potentiators and correctors of CFTR function that target the most common mutations that cause CF, such as Trikafta™ (elexacaftor / tezacaftor / ivacaftor) triple therapy (Vertex Pharmaceuticals™) (Fig 1).
However, there are no treatments available for individuals that have minimal function mutations (mutations lacking either a CFTR protein or a functional CFTR protein). Availability of more affordable treatment modalities can enhance positive patient impact, from both a quality of treatment and economic perspective.
DESCRIPTION OF THE INVENTION
Dr. Rommens and Dr. Strug are world leaders in the field and have decades of research experience working on Cystic Fibrosis. As a post-doctoral fellow, Dr. Rommens played an instrumental role in the discovery and characterization of the CFTR gene. She started her own lab at the Hospital for Sick Children and continued her research in CF working on genetic modifiers of CF. In collaboration with Dr. Strug, a leading statistical geneticist and Senior Scientist at SickKids, they identified a novel transporter, namely SLC26A9, in epithelial cells that provides alternative chloride transport, interacts with CFTR to enhance its function, and impacts the severity of CF across the affected organs (Fig 2).
Early observations suggest that activation of SLC26A9 is predicted to compensate for loss of CFTR function, irrespective of CFTR mutation. These population and functional studies highlight the potential of SLC26A9 agonists as potential therapeutics for CF.
Investigators have partnered with EVOTEC, a global contract research organization, and Toronto Innovation Acceleration Partners (TIAP) under the LAB150 Drug Discovery Program to identify and develop novel activators of SLC26A9. They successfully identified several hits, and these agonists are currently being developed as a potential treatment for CF and for other respiratory diseases such as COPD.
COMMERCIAL APPLICATIONS & ADVANTAGES
SLC26A9 targeted therapies address an unmet treatment need for CFTR patients with minimal function mutations. Based on the stage of development of the identified compounds, it is too early to assess their commercial potential and/or advantages as compared to available treatments. However, we anticipate that the development of alternative CFTR treatments can have significant patient and commercial impacts.
DEVELOPMENT STAGE
A high throughput screen in collaboration with EVOTEC, identified several small molecule hits as potential SLC26A9 enhancers. These hits are being evaluated and advanced as potential leads for the next stage of development (Fig 3). We are pursuing an aggressive patent strategy to ensure coverage of the identified compounds.
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