Awarded Grants

Led by Dr. Ilya Finkelstein, this project is developing an innovative gene editing technology called “retron editors” to target cystic fibrosis mutations that are unresponsive to current CFTR modulators. Unlike traditional methods, retron editors can safely replace entire segments of the CFTR gene, offering hope for individuals who do not benefit from existing therapies. The research aims to restore lung function by precisely correcting mutations with greater safety and efficiency.

Led by Dr. Andrei Korostelev at UMass Chan Medical School, this project is developing a new treatment for cystic fibrosis caused by nonsense mutations—genetic “stop signs” that prevent the production of full-length, functional CFTR protein. Using a highly targeted approach called readthrough antisense oligonucleotides (R-ASOs), the team aims to help cells ignore these faulty stop signals and restore proper protein function. With support from Emily’s Entourage, the project is working to refine and deliver this personalized therapy, bringing renewed hope to those with nonsense mutations of CF, who are part of the 10% of people with CF still waiting for mutation-targeted treatments.

Led by Dr. Anca Segall at San Diego State University, this project focuses on optimizing phage therapy to treat multidrug-resistant Achromobacter infections—an urgent and under-researched threat for people with CF and especially those who do not benefit from CFTR modulators. The team will identify the most effective phage-antibiotic combinations and study how Achromobacter evolves resistance, with the goal of re-sensitizing bacteria to antibiotics and improving treatment outcomes. This innovative approach has the potential to deliver life-saving therapies for the final 10% of the CF community still waiting for a breakthrough.

Led by Dr. David Liu at the Broad Institute of MIT and Harvard, this project aims to develop personalized prime editing strategies to correct around 100 cystic fibrosis (CF) mutations that currently have no approved CFTR modulator therapies. Using a high-throughput lentiviral screening technique combined with advanced computational modeling, the team will rapidly identify and optimize gene editing approaches tailored to each mutation. This research offers renewed hope for the final 10% of people with mutations that make them ineligible for CFTR modulators, accelerating the path to transformative treatments.

This project focuses on developing and applying bacteriophages to combat antibiotic-resistant pathogens in cystic fibrosis (CF), which are characterized by recurrent, treatment-resistant respiratory infections. By expanding phage collections, enhancing host ranges, and evaluating antibiotic-phage combination regimens, the project aims to establish a robust therapeutic arsenal and bring phage therapy into the clinic to combat antibiotic-resistant pathogens prevalent in people with CF.

Led by Dr. Paul McCray, this project aims to advance CF treatment by enhancing therapeutic cargo delivery using advanced AAV capsid variants. The team seeks to identify the most efficient capsids for delivering treatments to human airway epithelia and assess their efficacy. This innovative approach has the potential to provide curative outcomes for the 10% of people with CF who do not benefit from existing therapies.

This pilot study will test the effects of a combination of approved therapeutics that include the CFTR modulator, Trikafta, for CFTR mutations that are not responsive to CFTR modulators alone.

The project aims to create a partially humanized mouse airway for testing the efficiency of gene delivery methods. The team will then use this system to assess the ability of two specific agents to deliver genes to human airway epithelial cells: an Adeno-Associated Virus (AAV) vector and a lipid nanoparticle (LNP), with the goal of understanding delivery agent preferences for certain cell types of the human airway and the longevity of gene delivery effects.

Dr. Clarke’s research is focused on investigating novel strategies for correction of a rare CFTR gene variant in CF. His team’s research strategy includes various approaches to fully characterize and validate the design and delivery of novel splice-switching antisense oligonucleotides (ASOs) for the CFTR variant c.2988+1G>A, which is one of the most common CFTR variants in people with CF of African heritage, but is not addressed by currently available CFTR modulators. The data gained from the CF-Splice project is expected to provide a path to clinical benefit to people with CF in the real world, in particular to those of African ancestry, while paving the way to treat additional CFTR variants.

This project will optimize the multifunctional lipids to further improve their safety and efficacy for repeated aerosol delivery of a therapeutic plasmid DNA encoding CFTR gene and assess their in vitro and in vivo gene transfection and safety in an animal model. After demonstration of the efficacy of the proposed multifunctional ionizable lipids via aerosol delivery in this project, the researchers will further explore the LNP for systemic delivery of therapeutic nucleic acids to treat CF, which may produce more prolonged therapeutic efficacy than aerosol delivery. The optimized multifunctional ionizable lipids may provide a safe and efficient delivery platform for repeated local and systemic delivery of various nucleic acid therapeutics for treatment of the last 10% of people with CF.

This research explores the development of polymeric vehicles to improve the delivery of nucleic acid-based therapeutics to target tissues and cells in the body, primarily the lung and the gastrointestinal tract. The ultimate goal is to develop effective vehicles for targeted in vivo therapeutic nucleic acid delivery to epithelia in the lungs and gastrointestinal tract, addressing the unique challenges posed by the W1282X CF nonsense mutation.

While highly effective CFTR modulator therapies are now available to 90% of people with CF who have at least one copy of the most common genetic mutation, F508del, roughly 10% of the CF community with nonsense or other rare mutations of CF, do not benefit from these lifesaving therapies. Dr. Farinha’s work is focused on restoring CFTR protein for those in the final 10% of the CF community. His research aims to investigate altered genes and proteins and use them to find novel targets that can boost CFTR rescue in individuals with class I mutations.

With this grant, Professor Martin, in collaboration with the biotechnology company OmniSpirant Therapeutics, aims to advance the development of an inhaled gene therapy platform for CF. This technology is based on biological, non-viral nanoparticles called extracellular vesicles (EVs) that are produced from stem cells. Nonsense mutations of CF result in truncated and nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein. The gene therapy is engineered to transport and deliver a genetic, protein-making template for the full length CFTR protein, thus addressing CF at the genetic level.

Before a drug or treatment approach can be used in human clinical trials, it first needs to be tested in an animal model to assess safety and efficacy. However, no appropriate animal models with a cystic fibrosis transmembrane conductance regulator (CFTR) nonsense mutation are available to date. Previous studies demonstrate that the ferret is an ideal species for a CF model because it develops a lung disease that leads to respiratory failure and develops pancreatic diseases that lead to CF-related diabetes. This project will aim to generate a CF ferret model containing the W1286X mutation in the CFTR gene, similar to the human W1282X mutation. The ferret model will be used to test whether treatment using multiple drugs can reduce disease symptoms in the ferret. This new W1286X ferret model provides a new opportunity to accelerate the identification of effective and safe therapeutic approaches, significantly shortening the course of identifying new drugs or new therapeutic strategies for patients with CFTR-W1282X mutation, and potentially other nonsense mutations, in ways that cell-based systems or rodent models will not allow.

Gene-editing therapies that may be able to repair the defective gene associated with CF have the potential to achieve a permanent cure for the disease. There is currently a technology that can efficiently correct the mutation and restore the key protein that is involved with normal cell and lung function. However, it is difficult to deliver this therapy to the patient without it degrading in the body. This project will screen and identify pharmaceutical carriers — or materials for delivering the gene therapy cargo — that can protect it from degradation and, ultimately, be delivered to the lungs as inhaled medicines.

Mitochondrial dysfunction is an often overlooked issue in people with CF. It is marked by impaired energy production and the generation of huge levels of free radicals that are toxic to all cells in the body. Their work ​​represents a novel approach for CF in its use of a mitochondrial modulator, MP-101, to reduce free radical production and mitochondrial calcium overload, thereby reducing inflammatory responses and consequent tissue damage. MP-101 will be tested in a ferret model of CF and, if successful, could be tested in patients with CF.

Knowledge of CFTR function and cell type expression has advanced greatly since its discovery in 1989. Currently, 90% of people with CF benefit from mutation-targeted therapies that restore the function of their CFTR mutations. However, the remaining 10% of people with CF cannot benefit from these drugs because they produce too little or no functional protein. This project aims to achieve site-specific repair of CFTR mutations using an engineered enzyme, called an Adenine Base Editor (ABE). Dr. Sinn’s team will focus on delivering the ABE to enough of the appropriate airway cells to be therapeutic. The project will use naturally occurring particles, called extracellular vesicles (EVs), that most cells in the body produce. These particles are very small and have evolved to be cellular messengers that can deliver small molecules and proteins between cells. Dr. Sinn’s laboratory has previously demonstrated that EVs can deliver small RNAs and proteins to airway cells. As part of this grant, they will test if they can package and deliver ABEs to correct many of the rare, nonsense CFTR mutations.

Pulmonary bacterial infections, specifically drug-resistant infections, drive disease progression and mortality in people with CF. Among the worst are NTM infections, which are often resistant to available antibiotics and can disqualify individuals from lung transplantation at many transplant centers. In addition, these infections can be particularly dire in post-transplant patients taking immunosuppressive drugs. This project aims to explore bacteriophages, also known as phages, as a potential treatment option for people with NTM infections. Phages efficiently kill their bacterial hosts, have strong safety profiles, and can be used in conjunction with antibiotics with the possibility of additive, or even synergistic, benefits. Dr. Hatfull’s team will focus on identifying, preparing, and providing phages for compassionate use in the treatment of NTM infections in people with CF who have exhausted other treatment options. Their experiences will then be used to optimize phage screening, preparation, and stability.

Prime editing can write new genetic information into the genome in a very precise manner without causing damage to the host DNA, as no double-strand DNA breaks are induced. A growing body of evidence reports on the versatility, efficiency, and safety of prime editing, but further research is needed to investigate its potential for CF and its ability to correct CFTR mutations. This project explores the use of prime editing to correct specific CFTR mutations, the possibility to harness virus-like particles (VLPs) to deliver prime editing in a safe and efficient way, and whether VLPs can efficiently penetrate through CF mucus and enter and gene-edit CF airway epithelial cells.

This collaborative research project between teams at the University of Rochester Medical Center and University Medical Center Utrecht in the Netherlands aims to explore the use of ACE-tRNAs to produce full-length, fully functional CFTR protein. Previous studies on ACE-tRNA technology have shown promising results, indicating that further investigation of ACE-tRNAs in patient-derived cell models is now warranted. The two teams will work collaboratively to characterize CFTR function in patient-derived cells after ACE-tRNA treatment.

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.

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.  

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.

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.

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.

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.

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.

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.

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.

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.