Cystic Fibrosis Foundation Therapeutics (CFFT) — the non-profit arm of the Cystic Fibrosis Foundation (CFF) — and Pfizer have been collaborating since 2010 to discover new therapies for people with cystic fibrosis (CF). The six-year preclinical research program, in which the CFFT is investing up to $58 million, is almost at an end. The University of Iowa (UI) Research Foundation reached an agreement with Pfizer in 2016 to support the development of potential gene therapies for people with CF.

The genetic defect in cystic fibrosis

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a channel that transports chloride ions across cell membranes. This protein works to control water movement in tissues, resulting in the production of a thin mucus that protects and lubricates organs (e.g., lungs and pancreas) or entire systems (e.g., digestive).

If a mutation occurs in the CFTR gene that encodes this protein, chloride transport is unbalanced. The most common mutation in people with CF is the F508del mutation, where an amino acid is deleted in the 508 position, causing the protein to misfold and resulting in the production of a thick mucus that accumulates in vital organs. People with CF experience repeat infections and inflammation due to the accumulation of this thick mucus.

Pfizer’s therapeutic approach for treating CF

Pfizer’s preclinical research program with CFFT is focused on identifying new therapies to treat CF patients with a F508del mutation. The partnership is expected to take one or more compounds into clinic development. The approach is to develop CFTR modulators, which are small molecules that target the genetic defect in the CFTR protein.

The UI Research Foundation is working with Pfizer  to develop potential gene therapies for CF, with the aim of restoring CFTR gene function. In gene therapy, the correct copy of the gene is delivered to the mutated protein using a transport vehicle, usually a non-pathogenic virus. The research is being conducted in the laboratories of Professors John Engelhardt and Ziying Yan at UI, who helped to develop a viral vector system consisting of a hybrid of the adeno-associated virus (AAV) and the human bocavirus. This transport vehicle enters human airways, and delivers the gene that can restore CFTR function. In this collaboration, UI researchers will focus on testing the efficacy of this viral vector system using CF models, while Pfizer will develop packaging systems for the vector and optimize its manufacturing process.

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