Emily’s Entourage (EE) grants are aimed at top research talent pursuing high risk, high reward projects that have the potential to deliver breakthroughs to patients expeditiously. To date, EE has awarded over $4.8 million to multi-disciplinary teams around the world.
Catalyst for the Cure Grants
The Catalyst for the Cure Campaign is a groundbreaking initiative to raise $3 million in three years to fund four key research areas targeting Cystic Fibrosis (CF)-related nonsense mutations. These strategic areas were identified by the EE Scientific Advisory Board because they offer the greatest potential to accelerate development of cutting-edge treatments that can reach patients with nonsense mutations of CF within 5 years.
2020
Development of a Phage Lysin to Kill Methicillin Resistant Staphylococcus aureus (MRSA) both Nasally and in the Lungs of Cystic Fibrosis Patients
Vincent A. Fischetti, PhD
The Rockefeller University
Award Year: 2020
Bacterial resistance to current antibiotics is becoming an increasing problem resulting in more morbidity and mortality. In individuals with Cystic Fibrosis (CF), Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is frequently observed and causes infections in the noses that subsequently seed the lungs. In this project, the utility of phage lysins to control MRSA infections will be investigated. Lysins represent an alternative to antibiotics as they use a completely distinct mechanism from antibiotics in order to kill bacteria. For alternative bacterial species, resistance to lysins has not been observed. In addition, lysins can be delivered both systemically and via aerosol. Thus, MRSA-specific lysins may have advantages over conventional antimicrobial approaches, prevent chronic infections, and increase quality of life for people living with CF.
Catalyst for the Cure Strategy: Buying Time: Alternative Targets and Approaches
Antisense-mediated Exon Skipping to Upregulate W1282X-CFTR as a Spliced Variant
Adrian R. Krainer, PhD
Cold Spring Harbor Laboratory
Award Year: 2020
Cystic Fibrosis (CF) is caused by mutations that limit the functionality in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which can lead to respiratory failure. The W1282X nonsense mutation leads to the production of a shorter CFTR gene that is present in low levels, making it partially functional, due to a cellular quality-control mechanism called nonsense-mediated mRNA decay (NMD). This project utilizes a novel approach that includes targeting pre-mRNA splicing to remove exon 23—the region of the CFTR gene that contains the W1282X mutation—to increase the CFTR gene function in individuals with a W1282X mutation of CF. Thus, this project investigates this strategy by developing synthetic Antisense Oligonucleotides (ASOs) that can induce the skipping of exon 23 of the pre-MRNA sequence in order to achieve increased functionality in the mutated CFTR gene.
Catalyst for the Cure Strategy: Spell Check: Fixing Mutations Through RNA Editing
Personalizing MRSA Treatment – in vivo Delivery of Synthetic DNA Vaccines and Antibodies to Protect Against MRSA in Cystic Fibrosis
Ami Patel, PhD
The Wistar Institute
Award Year: 2020
People living with CF continue to be susceptible to bacterial infections and typically require extensive antibiotic regimens to maintain clear airways. Infections with methicillin-resistant Staphylococcus aureus (MRSA) are a lifelong challenge and new strategies are needed for control. This application will investigate two novel strategies to fight MRSA. The first approach aims to develop a vaccine for MRSA. Conventional vaccines employ protein fragments from a pathogen to produce an immune response. In contrast, this project will use synthetic DNA and rely on the human body to generate the protein fragment – an approach that has many advantages including activation of antibody and cell based immunity, and easier drug production and storage. The second approach will develop engineered antibodies against MRSA with enhanced antimicrobial activity relative to endogenous anti-MRSA antibodies. As in the first Aim, this study will use DNA to deliver the genetic information to encode these therapeutic antibodies, a strategy that enables sustained delivery and reduces drug costs. These approaches will initially be developed using a clinical isolate derived from a CF subject. It is anticipated that this personalized approach could be applied for other antimicrobial resistant bacterial pathogens that impact CF.
Catalyst for the Cure Strategy: Buying Time: Alternative Targets and Approaches
Development of a Collection of Anti-MRSA Phages as Alternatives to Antibiotics in Cystic Fibrosis
David T. Pride, MD, PhD, Robert ‘Chip’ Schooley, MD, Steffanie Strathdee, PhD
University of California San Diego Center for Innovative Phage Applications
Award Year: 2020
Individuals with Cystic Fibrosis (CF) are at great risk to develop recurrent lung infections. These infections are often caused by antibiotic-resistant bacteria like MRSA. This project aims to develop a panel of phage targeting MRSA that work collectively towards eliminating or reducing MRSA in the lungs of those with CF. By developing a well-characterized MRSA phage bank, this project will advance rational development of MRSA phage cocktails for use in the management of CF and make this collection widely available to physicians and researchers across the globe to facilitate life-saving phage therapy.
Catalyst for the Cure Strategy: Buying Time: Alternative Targets and Approaches
2019
W1282X Cystic Fibrosis Mouse Model Development and Utilization
Craig Hodges, PhD
Case Western Reserve University
Award Year: 2019
Models that enable testing of new therapies to treat CFTR nonsense mutation are needed. Craig Hodges and colleagues at Case Western Reserve University are creating new mouse models that contain the W1282X mutation in the CFTR gene. Several CF mouse models exist, including models that contain the F508del, G551D or G542X mutations. The objective of this proposal is to generate well characterized models that can be distributed to laboratories (academic or industry) focused on developing or testing of therapeutic strategies specifically for the W1282X mutation, or for CF nonsense mutations in general.
Catalyst for the Cure Strategy: Building a Toolbox: Understanding the Biology and Developing Models of Nonsense Mutations
Eliminating Resistance in MDR Bacteria Using Phage Therapy
Benjamin Chan, PhD, Jonathan Koff, MD, Paul Turner, PhD
Yale University
Award Year: 2019
S. aureus is a multi-drug resistant (MDR) bacteria that causes pulmonary infections in individuals with CF starting at a young age. Infections caused by MDR bacteria directly contribute to morbidity and mortality as physicians are forced to rely on a diminishing arsenal of antibiotics. In those persistently infected with S. aureus, reduction in the bacterial burden could have significant positive impact on lung function, pulmonary exacerbations, and quality of life. Phage therapy harnesses bacteriophages (bacteria-specific viruses) that target and kill bacteria. When used therapeutically, these phages are able to kill bacteria expressing specific virulence factors that enable them to cause infection. Funding from EE will enable further development efforts of phage-based therapeutics in treating CF-associated infections.
Catalyst for the Cure Strategy: Buying Time: Alternative Targets and Approaches
Delivering Genetic Therapeutic Repair of CFTR Nonsense Mutations
James Dahlman, PhD
Georgia Tech
Award Year: 2019
Delivery of nucleic acids to the lungs, including tRNAs, is a promising alternative approach for CF therapy. However, targeting nucleic acids to the appropriate cells in the lung remains a major challenge. Using state-of-art approaches, the Dahlman lab aims to evolve optimized lung-specific delivery agents called nanoparticles to facilitate nucleic acid delivery. The overall goal of this project is to accelerate the rate at which nanoparticles can be used to treat CF.
Catalyst for the Cure Strategy: Spell Check: Fixing Mutation Through RNA Editing
Measuring Therapeutic Repair of CFTR Nonsense Mutations
John Lueck, PhD
University of Rochester
Award Year: 2019
The stimulus funding from Emily’s Entourage will be used to purchase a specialized piece of equipment, called Ussing chambers, which are the gold-standard way to measure CFTR activity in airway epithelial cells and determine the effectiveness of developmental CF therapeutics. Specifically, Ussing chambers will be used to test the effectiveness of nonsense suppressing ACE-tRNAs, developed through a previous research grant from Emily’s Entourage.
Catalyst for the Cure Strategy: Spell Check: Fixing Mutations Through RNA Editing
2018
Efficacy of CFTR modulators on W1282X-CFTR mutation in intestinal organoids
Jeffrey Beekman, PhD University Medical Center Utrecht, Netherlands Award Year: 2018
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.
Catalyst for the Cure Strategy: Browsing the Library: Identifying and Repurposing Therapeutic Molecules
Novel therapeutic approaches for treatment of CF patients with the W1282X premature termination codon mutation
Venkateshwar Mutyam, PhD Steven M Rowe, MD, MSPH University of Alabama at Birmingham Award Year: 2018
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.
Catalyst for the Cure Strategy: Browsing the Library: Identifying and Repurposing Therapeutic Molecules
Improving W1282X CFTR airway epithelial cell function with small molecules
Theo Moraes, MD, PhD
Tanja Gonska, MD
Christine Bear, PhD
Felix Ratjen, MD, PhD, FRCPC
SickKids, Toronto Canada Award Year: 2018
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.
Catalyst for the Cure Strategy: Browsing the Library: Identifying and Repurposing Therapeutic Molecules
A Molecular Prosthesis for CFTR-Independent treatment of CF caused by nonsense mutations
Martin D. Burke, MD, PhD Michael J. Welsh, MD University of Illinois at Urbana-Champaign University of Iowa Award Year: 2018
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.
Catalyst for the Cure Strategy: Creative Workarounds: Working with Alternative Pathways
2017
Novel approaches to improve W1282X-CFTR functional expression in airway epithelia
Gergely L. Lukacs, MD, PhD McGill University Award Year: 2017
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.
Catalyst for the Cure Strategy: Building a Toolbox: Understanding the Biology and Developing Models of Nonsense Mutations
Creating the W1282X-CFTR airway epithelial cell toolbox
Scott H. Randell, PhD Finn Hawkins, MBBCh University of North Carolina at Chapel Hill Boston University Award Year: 2017
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.
Catalyst for the Cure Strategy: Building a Toolbox: Understanding the Biology and Developing Models of Nonsense Mutations
Advancing small molecules to restore W1282X-CFTR function
Alan S. Verkman, MD, PhD University of California, San Francisco Award year: 2017
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.
Catalyst for the Cure Strategy: Browsing the Library: Identifying and Repurposing Therapeutic Molecules
Using SPX-101 to normalize airway hydration in W1282X-CFTR epithelia
Robert Tarran, PhD University of North Carolina at Chapel Hill Award Year: 2017
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.
Catalyst for the Cure Strategy: Creative Workarounds: Working with Alternative Pathways
Therapeutic repair of CFTR nonsense mutations
Christopher Ahern, PhD University of Iowa Award Year: 2017
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.
Catalyst for the Cure Strategy: Spell Check: Fixing Mutations Through RNA Editing
Strategic Investments
Spirovant Sciences (formerly Talee Bio)
University of Iowa and Militia Hill Ventures Beverly L. Davidson PhD John F. Engelhardt, PhD Paul B. McCray, Jr, MD Michael Welsh, MD Joseph Zabner, MD Jane H. Hollingsworth Joan Lau, PhD, MBA Eric Yuen, MD Award Year: 2017
Through a unique partnership with the University of Iowa and Militia Hill Ventures, Emily’s Entourage provided seed funding to launch Spirovant Sciences (formerly 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.
Pilot Grants
This program is administered through and matched by the Penn Medicine Orphan Disease Center’s Million Dollar Bike Ride Pilot Grant Program.
Rational design of effective therapeutics for treatment of the 1282X CFTR disorder
Barry Cooperman, PhD University of Pennsylvania Award Year: 2016
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.
Novel assay platforms and therapies for W1282X-CFTR
Christine Bear, PhD The Hospital for Sick Kids, Toronto, CA Award Year: 2015
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.
N-of-1 trials to validate therapies for W1282X-CFTR
Steven M. Rowe, MD, MSPH University of Alabama Award Year: 2015
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.
Independent Grants
Small molecules to rescue the W1282X mutation in CFTR
Alan S. Verkman, MD, PhD University of California, San Francisco Gergley L. Lukacs, PhD McGill University Award Year: 2015
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.