Awarded Grants

Using innovative biochemical techniques, the major aim of this project is to identify new targets to improve trafficking of CFTR1281, the truncated protein product that results from the W1282X mutation.

The absence of validated cell models has been a major barrier to the development of therapies for CFTR nonsense mutations. Scott H Randell, PhD, in collaboration with Finn Hawkins, MBBCh (Boston University) will develop W1282X homozygous airway epithelial cell models that should expedite therapeutic developments.

This project employs pioneering high throughput screening approaches to identify drug-like molecules that target W1282X-CFTR, and other rare CF mutations. In studies previously funded by Emily’s Entourage, Dr. Verkman established the concept that combined “correctors” and “potentiators” –  as used to treat the most common CF mutation, F508del– could also be used to treat the W1282X mutation. These new studies aim to progress this area.

A key characteristic of CF is thick, dehydrated mucus that accumulates in the lungs causing chronic bacterial infections. In patients with CF, an overactive protein called ENaC contributes to airway surface dehydration to drive this process. This project will investigate a novel therapeutic approach to rehydrate the airways using a preclinical candidate that inhibits ENaC.

This project uses an innovative genetic approach to correct the W1282X-CFTR mutation. Engineered transfer-RNA molecules will be used to direct delivery of an appropriate tryptophan (W) to the W1282X mutation during protein synthesis to promotes production of the full length CFTR protein.

The goal of this project is to investigate if current or investigational CFTR modulators are effective in organoids derived from CF subjects with the W1282X mutation. 

Prior studies supported by Emily’s Entourage revealed that KALYDECO provides therapeutic benefit in some CF subjects with the W1282X mutation. These provocative studies will be extended in further n-of-1 clinical trials to assess whether clinical benefits can be further enhanced by an approved corrector-potentiator therapy.

Combining expertise in cell culture, CFTR functional assessment, therapeutic development, and clinical practice, this project will assess whether available therapeutic approaches modulate key properties, including ion transport and mucociliary clearance, in airway epithelial cells derived from CF subjects with the W1282X mutation.

CF is caused by loss of function of the CFTR ion channel. Development of alternative ways to restore missing channel function independently of CFTR is an urgent unmet medical need. Based on compelling studies in cell culture models and in CF animal models, this project will test a novel therapeutic strategy to directly address this need. This approach uses a drug approved for an alternative indication and could eventually lead to development of a novel therapeutic approach for CF.

Through a unique partnership with the University of Iowa and Militia Hill Ventures, Emily’s Entourage provided seed funding to launch Talee Bio, a biotech company focused exclusively on gene therapy to cure all mutations of CF. In a race against the clock, this venture philanthropy model can expedite advances by harnessing the power of venture capital.

Using synthetic chemistry in conjunction with biochemical approaches, the aim of this project is to identify the site of action of Ataluren, a drug that promotes premature stop codon readthrough, and to develop improved chemical analogs of this drug candidate.

This project considered two distinct areas to advance W1282X-CFTR targeted therapeutic development. The first objective was to develop assays of CFTR function in patient-derived cell samples to test efficacy of existing and new CF therapies. The second considered a novel genetic approach to overcome the W1282X mutation.

The objective of this project was to assess current therapeutic options for the W1282X-CFTR mutation in a patient-specific manner. The major outcome of this study, reported in the Journal of Cystic Fibrosis, indicated that the potentiator Ivacaftor elicited CFTR-dependent current in a W1282X-CFTR subject.

This project aimed to establish a novel paradigm for therapy for the W1228X-CFTR mutation. Studies developed initial small molecule discovery platforms and provided the first evidence that a combined “correctors” and “potentiators” — as used to treat the most common CF mutation, F508del — could also be used to treat the W1282X mutation.