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Big strides in the battle against cystic fibrosis

Gene editing in animals shows promise
Big strides in the battle against cystic fibrosis hero image

The Takeaway: Cystic fibrosis is an inherited disease that causes the body to produce a thick, sticky mucus that can build up in the lungs as well as the pancreas and intestines. Typically diagnosed in early childhood, symptoms and their severity can vary widely from person to person, but tremendous advancements in cystic fibrosis care are improving the quality of life for those who have this disease. Recent breakthroughs offer even more hope.

What is cystic fibrosis?

Cystic fibrosis (CF) is a genetic disorder that primarily affects the respiratory and digestive systems. It is a life-limiting condition caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This gene encodes a protein that plays a crucial role in maintaining the balance of salt and water on the surface of cells, particularly in the lungs and digestive tract.

The CFTR protein is responsible for regulating the flow of chloride ions across cell membranes. In individuals with cystic fibrosis, mutations in the CFTR gene lead to the production of a defective protein, causing the abnormal transport of chloride ions. This disrupts the normal balance of salt and water, resulting in the production of thick and sticky mucus. This viscous mucus clogs the airways in the lungs and ducts in the pancreas, liver, and intestines, leading to a range of symptoms and complications.

One of the hallmark features of cystic fibrosis is respiratory problems. The thick mucus obstructs the air passages in the lungs, making it difficult for individuals with CF to breathe. Persistent coughing, wheezing, and recurrent lung infections are common manifestations. Over time, chronic inflammation and infection can cause irreversible damage to the lung tissue, leading to respiratory failure.

The digestive system is also profoundly affected by cystic fibrosis. The pancreas, an organ responsible for producing enzymes essential for digestion, becomes clogged with thick mucus. As a result, individuals with CF often experience malabsorption of nutrients, leading to poor growth and nutritional deficiencies. Additionally, liver disease may develop due to the obstruction of bile ducts by thickened secretions.

Cystic fibrosis is an inherited condition, and both parents must carry a faulty CFTR gene for their child to be affected. If both parents are carriers, there is a 25% chance with each pregnancy that the child will inherit two copies of the mutated gene and, therefore, have cystic fibrosis. Individuals who inherit one copy of the faulty gene are carriers but do not typically exhibit symptoms of the disease.

Diagnosis of cystic fibrosis often occurs in early childhood, either through newborn screening or when symptoms become apparent. Sweat tests, genetic testing, and imaging studies are commonly employed to confirm the diagnosis. Although there is no cure for cystic fibrosis, advances in medical care have significantly improved the prognosis and quality of life for individuals with the condition.

Treatment strategies for cystic fibrosis are comprehensive and aim to manage symptoms, prevent complications, and improve overall well-being. This often involves a multidisciplinary approach, including medications to thin mucus, physical therapy to help clear airways, and nutritional support to address malabsorption. Lung transplantation may be considered in severe cases where respiratory function is severely compromised.

Research into cystic fibrosis continues to expand our understanding of the disease, and innovative therapies, including gene-editing techniques, are being explored. The development of modulator drugs, which target specific mutations to enhance the function of the CFTR protein, represents a significant breakthrough in treating the underlying cause of the disease.

Breakthrough award honors effective CF medicines

In September, the Breakthrough Prize Foundation announced the winners of the 2023 Breakthrough Prizes.

The Breakthrough Prize is an annual set of international awards that recognize outstanding achievements in fundamental physics, life sciences, and mathematics. Established in 2012 by a group of Silicon Valley entrepreneurs, the Breakthrough Prizes aim to celebrate and reward scientists and mathematicians who made significant contributions to their respective fields.

The Life Sciences Breakthrough Prize recognizes achievements in the fields of genetics, molecular biology, and neurobiology. Each prize comes with a monetary award.

This year, the life sciences award included a nod to Sabine Hadida, Paul Negulescu, and Fredrick Van Goor, all of whom work at Vertex Pharmaceuticals. The trio invented the first effective medicines to treat the underlying cause of cystic fibrosis. These researchers discovered four medicines, the latest of which is a triple combination medicine that enables the protein to function, which greatly improves quality of life–and length of life–for people with select CF genes.

That drug, Trikafta, is now used by 90 percent of people with cystic fibrosis.

Study: Overcoming gene editing challenges for cystic fibrosis patients

A recent study, led by University of Iowa scientist with contributions from IDT researchers and published in Nature Communications, highlighted a workaround for challenges associated with CF—that gene editing strategies often run into problems with the complex nature of airways.

In this study, researchers abandoned previously used shuttle peptides in favor of an improved solution, called the S315. Using rhesus monkeys, researchers delivered a Cy5-labeled peptide using intratracheal aerosol delivery, which successfully spread through the respiratory tract. Problem genes were targeted using base editor ribonucleoprotein complex (RNP), resulting in successful editing in the monkey’s airway epithelia. Follow-up tests showed evidence of the edited epithelia remaining for at least 12 months. In addition to in vivo studies, the research team also demonstrated the restoration of anion channel function by delivering the base editor to cultured human airway epithelia.

“We demonstrated base editing and characterized immune responses following non-viral delivery to the young rhesus monkey model, which has airway anatomy and physiology that closely represents humans,” the authors wrote. “We also established that screening of peptides in the air-liquid interface culture model of well-differentiated human airway epithelia successfully identified shuttle peptides with improved in vivo delivery properties. The delivery of base editors as RNPs offers advantages as the duration of exposure to the editing agent is short and ends as the protein is degraded.”

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