Porosome therapy targeting CFTR shows promise in disease models

Treatment aims to bring healthy protein into the cells of CF patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Mice are shown investigating beakers and other lab equipment.

A novel treatment strategy for cystic fibrosis (CF) that’s based on a cellular structure called the porosome showed promise in cell and animal models of CF caused by the common F508del mutation.

In the cell model, this approach was more potent than tezacaftor and ivacaftor, which are CFTR modulators used in approved CF therapies, according to data presented by Porosome Therapeutics, the company developing the approach.

Findings were showcased at the April summit of the American Physiological Society in Long Beach, California, in the poster “Cystic fibrosis rescued using a reprogrammed porosome secretory machinery.”

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The porosome is a complex of proteins, including CFTR

“These new results mark a major breakthrough in our efforts to find a path to a cure, not only for CF but for a wide range of debilitating diseases and chronic conditions,” Guillermo Marmol, president and CEO of Porosome Therapeutics, said in a press release sent to Cystic Fibrosis News Today. Marmol noted that the company is focused on bringing this approach into clinical testing in people.

“We are diligently conducting further studies to comprehensively assess the safety, stability, and optimal dosage of this approach,” said Bhanu P. Jena, PhD, the company’s founder and chairman.

CF is caused by mutations in the gene that encodes the CFTR protein. This protein normally helps regulate the flow of chloride ions across the cell membrane. Problems in the workings of CFTR lead to the production of abnormally thick, sticky mucus, which builds in organs to drive most disease symptoms.

The porosome is a complex of dozens of proteins, including CFTR, that work together to regulate the movement of molecules out of cells. The therapeutic approach described here basically involves taking porosomes from cells with healthy CFTR protein and transplanting them into CF cells.

“Reconstitution of functional porosomes having normal CFTR, therefore holds great promise in treating CF with all different types of CFTR mutations,” the researchers wrote.

In CF mouse model, treatment ‘rescued’ chloride secretion in nasal passages

Researchers first tested this approach in a cell model of CF caused by the most common CF-causing mutation, F508del. As in CF patients, cells in this particular model characteristically secrete lower-than-normal levels of certain mucus proteins, including MUC5B and MUC5AC.

The porosome-based treatment increased secretion of these mucus proteins from CF cells. Notably, the porosome therapy had a significantly more potent effect on mucus protein secretion compared to tezacaftor and ivacaftor, which in CFTR modulators work by boosting the functionality of the faulty CFTR protein.

These findings indicate that “porosome-reconstitution therapy is a powerful approach,” the researchers wrote.

Scientists next tested the porosome-based treatment in a mouse model of CF caused by the F508del mutation.

In these experiments, they evaluated the effect of the treatment on CFTR function using a well-established measure called the nasal potential difference, which records the small electrical charge that occurs in the airway lining inside the nose. Results indicated that the porosome therapy normalized CFTR function.

“Porosomes obtained from functional [healthy] human bronchial epithelial cells were used to treat the nasal passages of CF-affected mice. Remarkably, within 24 hours of treatment, this reconstitution of the porosome rescued chloride secretion in the nasal passage,” Jena said.