Potential cystic fibrosis treatment uses ‘molecular prosthetic’ for missing lung protein — ScienceDaily

Approved drugs commonly used to treat fungal infections can also function as protein channels that are missing in the lungs of patients with cystic fibrosis and run as prostheses on molecular weight tables . University of Illinois and the University of Iowa.

Cystic fibrosis is a lifelong disease that predisposes patients to lung infections. There are treatments for some but not all patients and there is no cure. The drug restores the anti-infective properties of human patients and lung tissue donated by cystic fibrosis pigs. It has the potential to be the first treatment to address all types of cystic fibrosis, regardless of the genetic mutations that cause protein deficiency.

The researchers published their findings in the journal Nature .

"We are using a small molecule substitute that can function as a missing protein channel, rather than trying to do gene therapy – this treatment has not yet worked in the lungs – or correcting the protein. We call it molecular repair, “Research leader Dr. Martin D. Burke said. Burke is a professor of chemistry at Illinois and associate dean of research at the Carl Illinois School of Medicine.

A healthy lung has a layer of fluid on the surface of the airway that helps prevent infection. Cells in the lung intima secrete bicarbonate or baking soda into the liquid, making it unsuitable for invading bacteria. However, in people with cystic fibrosis, proteins (called CFTR) that discharge bicarbonate to the surface in the cell membrane are completely defective or absent.

"The loss of CFTR channel function makes the airway surface fluid more acidic and destroys salt. These defects weaken two important lung defenses: antibiotic activity of airway fluids and mucus clearance. As a result, people become susceptible to infection. "The co-author of the study is Dr. Michael Welsh, a professor of internal medicine at Carver School of Medicine, Iowa, and a research fellow at the Howard Hughes Medical Institute.

Burke's team has long studied the channel formation properties of drugs used to treat the fungal infection drug am-foe-TARE-is-in. In this new study, the researchers explored it as a treatment candidate for cystic fibrosis. They found that amphotericin can form a channel in the surface membrane of lung tissue donated by patients with cystic fibrosis caused by various mutations in the CFTR gene. The channel releases bicarbonate accumulated in the cells, returning the pH and thickness of the airway surface liquid to a normal range.

The researchers also used amphotericin formulated for delivery to the lungs to treat pigs with cystic fibrosis. In both experiments, in human tissue and pigs, the researchers saw the recovery of anti-infective properties in the fluid on the surface of the lung.

"Like a simple prosthetic device that restores many functions for those who have missing limbs, we have found that although amphotericin is not a perfect mimetic of CFTR protein, it acts as a bicarbonate channel and restores it. The defense mechanism. The airway surface liquid," Burke said.

Unlike drugs that target defective CFTR proteins and correct their misfolded structures, molecular repair methods bypass defective proteins to form new channels – an important factor for patients with cystic fibrosis who are completely deficient in CFTR. Characteristic proteins, therefore cannot be treated with a calibrated drug.

"Although many recent advances in cystic fibrosis treatment target specific mutations, regardless of the mutation, this approach benefits everyone with cystic fibrosis," a common share of non-profit cystic fibrosis. Founder Emily Kramer-Golinkoff said. The research foundation Emily's Entourage, which partially funded the study. “Secondly, and perhaps more importantly, this approach provides an opportunity to re-use existing, approved drugs and bring them to the clinic quickly.”

Next, the Illinois-Iowa Joint Research Group will conduct clinical trials to determine whether amphotericin delivered to the lungs is effective for people with cystic fibrosis.

"Because amphotericin is an approved drug, the clinical translation pathway is more straightforward. It has been proven that when delivered directly to the lungs it is safe and it does not enter other parts of the body, so We can avoid the negative side effects of this drug," Burke said. "We want to conduct clinical trials as soon as possible, especially those who are not good for the corrector."

"The cystic fibrosis community does need new therapies to alleviate the burden of this disease. We are interested in understanding how this potential treatment will perform in future clinical trials," said Dr. James Kiley. The Department of Pulmonary Diseases of the National Heart, Lung and Blood Institute, part of the National Institutes of Health, also funds this work.

Watch Burke's video explaining the findings at https://uofi.app.box.com/v/cfvideo .

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