Emily’s Entourage Awards $790K to Support Work on CF Therapeutics

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by Marta Figueiredo, PhD |

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Nonprofit Emily’s Entourage has awarded a total of $790,000 to four research projects focused on potential therapies for cystic fibrosis (CF) and related lung infections.

To be given over two years, the four grants “focus on two critical unmet needs for the CF community: therapies that address nonsense mutations of CF and treatments for life-threatening lung infections,” Emily Kramer-Golinkoff, the organization’s co-founder and a CF nonsense mutation patient, said in a press release.

“At Emily’s Entourage, we remain laser focused on filling those gaps as people with CF, and especially those without targeted therapies, do not have time to wait,” she added.

CF is caused by mutations in the CFTR gene, resulting in the production of a faulty CFTR protein. One type of CF-causing mutation, known as a nonsense mutation, leads to a premature stop in protein production, resulting in a shorter, non-functional or poorly functional CFTR protein.

Despite increasing advances in therapeutic options for CF, including those targeting common CTFR mutations, there are still no disease-targeting therapies available for people with less common nonsense mutations, who account for about 10% of all CF cases.

This was the fifth round of grants supported by Emily’s Entourage’s Catalyst for the Cure fund, which awards projects showing the greatest potential to advance developing cutting-edge therapies that can reach this subgroup of CF patients.

One of the awarded projects, titled “A Novel Approach to Remove the W1282X Mutation to Increase CFTR Function,” will focus on the second most common CF-causing nonsense mutation, called W1282X.

Led by Adrian R. Krainer, PhD, the team at Cold Spring Harbor Laboratory in New York will test a new approach that involves the targeted editing of the premature version of CFTR’s messenger RNA (pre-mRNA), the molecule derived from DNA and used as template for protein production.

Researchers want to identify antisense oligonucleotides to promote the skipping of the pre-mRNA segment resulting from the W1282X mutation, preventing the premature stop in protein production and increasing CFTR’s functionality.

The other three projects aim to develop therapeutic alternatives to antibiotics to manage antibiotic-resistant lung infections — particularly methicillin-resistant Staphylococcus aureus (MRSA) — to which CF patients are more susceptible. The results could benefit people with any CF-causing mutation, including but not limited to nonsense mutations, the organization states in the release.

One of the projects, titled “Development of a Collection of Anti-MRSA Phages as Alternatives to Antibiotics in CF,” will be led by David T. Pride, MD, PhD; Robert ‘Chip’ Schooley, MD; and Steffanie Strathdee, PhD, of the University of California San Diego’s Center for Innovative Phage Applications.

Based on the principle of phage therapy, the team aims to identify and develop a panel of bacteriophages (or phages) — viruses that specifically infect and destroy bacteria while not harming human cells — specifically targeting MRSA.

By making this collection widely available to physicians and researchers around the world, the team’s goal is to help in the development of MRSA-targeted phage cocktails to manage life-threatening MRSA infections in people with CF.

In another project, “Development of a Phage Lysin to Kill MRSA in the Nose and Lungs of CF Patients,” researchers at The Rockefeller University in New York will also take advantage of phages for the treatment of MRSA. Led by Vincent A. Fischetti, PhD, the team will investigate the utility of MRSA-specific phage lysins.

Lysins are enzymes naturally produced by phages to break down a key component of the bacterial cell wall, leading to the rapid disintegration of bacteria. Lysins can be delivered both systemically and via aerosol.

MRSA-specific lysins have the potential to be superior to conventional antimicrobial approaches, preventing chronic infections and increasing CF patients’ quality of life.

Ami Patel, PhD, of The Wistar Institute in Philadelphia will lead the third project, titled “Novel Personalized Treatment Approaches to Protect Against MRSA in CF.” Researchers will evaluate the effectiveness of two new approaches to fight MRSA: one based on a vaccine and another on engineered antibodies against MRSA.

Both strategies will deliver lab-made DNA and rely on the human body to generate the molecule of interest.

Conventional vaccines deliver “harmless” protein fragments of a particular bacteria to induce an immune response and memory of that bacteria so that in the likelihood of exposure, the body is able to promote a prompt immune reaction against it.

Instead of using protein fragments, the potential new vaccine will deliver DNA specifically engineered to promote the production of a MRSA protein fragment by the patient’s own body.

In the second approach, engineered DNA will promote the production of antibodies against MRSA with increased antimicrobial activity, compared with the naturally produced antibodies.

This type of DNA-based approach has several advantages, including activation of several types of immune responses (in the case of the vaccine), easier production and storage, and reduced costs.

These approaches will initially be developed using a MRSA isolated from a CF patient. The team anticipates that this personalized approach could be applied to other antibiotic-resistant bacteria affecting people with CF.

Since it was founded in 2011, Emily’s Entourage has awarded more than $4.8 million to 21 multidisciplinary projects around the world.

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