A study published in Nature Communications revealed a new antisense oligonucleotide (ASO) therapy applicable to the W1282X mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in cystic fibrosis (CF). This new therapy resolved the nonsense-mediated mRNA decay (NMD)-degradation of mRNA that occurs in CF and that has prevented the success of treatments.

Among the new therapies based on molecules that control protein function, ASO technology stands out. These have already been successful in various illnesses, like spinal muscular atrophy (SMA). CF is a disease caused by a deficiency in the CFTR gene, which can be due to many different mutations.

The problem for CF patients is that they do not make enough CFTR protein. The new approach proposed by Adrian Krainer, and his collaborators at Stony Brook University and the Division of Human Genetics, Children's Hospital of Philadelphia, opens the door to the clinical development of a therapy for the W1282X mutation. The treatment is delivered to human bronchial epithelial cells and consists of a three-ASO cocktail that increases CFTR-mediated chloride current by increasing the expression of CFTR-W1282X mRNA and CFTR protein.

This leads to the production of a truncated but functional version of CFTR. This situation does not occur in patients who have the W1282X mutation. In these patients, the defective protein synthesis pathway does not end. ASOs are small fragments of oligonucleotide that binds mRNA to block the translation of a protein. The ASOs designed by Krainer interfere with the elimination signal of defective proteins and achieve the synthesis of truncated CFTR proteins. These truncated proteins partially retain function, but this is enough to improve lung cell function and relieve symptoms.

"Truncated CFTR is less active than normal CFTR, but it has residual activity, which can be beneficial. The problem is that very little truncated protein is made, because the mutant CFTR mRNA is unstable. Our ASO approach stabilizes the mRNA, allowing more of the truncated protein to accumulate," Krainer told BioWorld Science.

Because nonsense-mediated decay is a broad quality control mechanism in cells, broadly inhibiting this process would likely cause more problems than it solves. The three-ASO cocktail that Krainer and his colleagues developed specifically targeted the CFTR-W1282X mutation.

CF is an autosomal recessive hereditary disease that affects more than 80,000 people worldwide. Its origin is in the deficient function of the CFTR gene. This gene modifies the protein that controls the entry of chlorides into the epithelial cells that line the organs, which produces thick mucus in the lungs, occluding them and causing breathing problems. This condition also increases the risk of bacterial infections and can cause severe lung damage or death.

This gene can have different mutations that determine the severity of the condition. The lungs are not the only organs affected. Thicker than normal secretions are also produced in the sweat glands, pancreas, liver, intestines, paranasal sinuses and sexual organs, whose ducts become clogged and do not work correctly.

Therefore, the complications associated with this disease are very diverse. In the airways, it can cause bronchiectasis, hemoptysis, pneumothorax or respiratory failure; in the digestive system, diabetes, liver disease or intestinal obstructions. In other cases, it is also accompanied by infertility or osteoporosis.

Although there is no cure and some young patients die before reaching maturity or in their 30s, treatments have improved considerably in recent years. Now the quality of life of these patients is better than several decades ago, and survival has increased to 50. The goal is for the disease to become chronic.

CF treatments are very diverse, depending on the mutation that the patient presents, the affected organs and their complications. In the literature, we can find more than 1,300 mutations described for the CFTR gene, so ASO-based therapies are indicated for cases in which other treatments that modulate CFTR do not exist.

"Our focus was on a specific CF mutation, W1282X, for which therapies are not currently available. Our study provided in vitro proof of concept for such a therapy, but in vivo experiments have not yet been undertaken," Krainer stated.

It is not the first ASO-based therapy that Krainer has developed.

"We previously worked on the development of Spinraza (nusinersen), an ASO for spinal muscular atrophy (SMA). Spinraza was approved by the FDA at the end of 2016, and it has already helped more than 11,000 SMA patients," Krainer remarked. His discovery is being used already for related pathologies. "Other ASOs have been approved for Duchenne muscular dystrophy, familial hypercholesterolemia and hereditary transthyretin amyloidosis. Several others are currently under development for a variety of diseases," he said.

Krainer's group is exploring this line of research to treat other pathologies. "We continue to explore various therapeutic applications of ASO for genetic diseases and oncology, based on fundamental mechanisms of mRNA processing," he commented.