Gene-product therapy a success in cystic fibrosis treatment: review

Professor John Wilson AM is using gene-product modulating
therapy for treatment of patients with cystic fibrosis

by Anne Crawford

Gene-product modulating therapy – treatment addressing gene abnormality by acting on the proteins arising from the gene rather than trying to correct the gene itself – has been attracting considerable scientific attention in recent years.

Monash University’s Professor John Wilson AM, who is using this approach to treat patients with cystic fibrosis, recently reported on the therapy in a comment piece published in Gene Therapy Nature.


The therapy is one of three ways of addressing disease with genetic causes. The other two are: gene therapy, which replaces, correct or edits genes; and conventional medicine treating the symptoms or functional impairments that arise from gene abnormality.

“Gene-product modulating therapy looks at the product of the gene and tries to restore function to this product,” Professor Wilson said. “It changes the way the protein product folds inside the body after being made by the gene.

“The evidence that this treatment is successful primarily comes from the treatment of cystic fibrosis,” he said.

Cystic fibrosis (CF), an inherited disease that progressively causes severe damage to the respiratory and digestive systems, is the most common lethal genetic mutation genetic mutation in Caucasians and affects more than 3000 Australians. Around 75,000 Australians carry the gene.

Professor Wilson, Head of CF Service at AlfredHealth, said new drugs could restore the shape of particular gene products, allowing researchers to correct abnormalities in their structure and function in the human body before they actually occur.

“There has been a rapid change in the number and effectiveness of gene-modifying agents that restore the function of the protein to a significant level which improves the quality of life, lung function and longevity,” he said.

Research conducted by Professor Wilson, a respiratory physician, and his group over the past 25 years has made important contributions to cystic fibrosis care. The researchers described a number of manifestations of the illness outside the lung; showed a clear link between the disease and increased risk of gastro-intestinal cancer; and demonstrated that having the CF gene is a contributing factor to osteoporosis in affected patients.

“We were the first to describe the effect of the CF gene on kidney functions and have now shown that having cystic fibrosis impairs cardiovascular function and cognition.”

The use of gene-modifying agents in Professor Wilson’s patients began with clinical trials.

“Over successive years we’ve been fortunate enough to show that these new drugs have very few, if any, side-effects, are well-tolerated by patients and have significantly improved their quality of life,” he said.

“We’ve also shown that these agents improve exercise capacity, most likely through multiple mechanisms including cell processes that regulate chloride transportation as well as through improved energy function (“energetics”), both important processes.”

Chloride transportation is responsible mainly for normal airway function in the lungs, and energetics regulate the conversion of oxygen and glucose into energy in cells of the body.

“In terms of lung disease the gene-modulating agents have unequivocally shown better lung function survival in those subjects eligible to take them,” Professor Wilson said. “We have also shown a wide range of other body system problems that occur can be improved by gene-modulating therapy as well, particularly exercise tolerance and cognitive function.

“We’ve already seen a significant reduction in the need for hospital admissions and lung transplantation in our growing patient population.”

Professor Wilson is now developing a diagnostic blood test in conjunction with the Murdoch Institute to see whether individual patients affected by cystic fibrosis will benefit from one or more of the new gene-modulating treatments without them having to to through lengthy clinical trials testing drugs that may or may not be effective for them.

Monash University is supporting a patent application for the test.

Professor Wilson has received clinical trial support and consultancy funding from Vertex Pharmaceuticals Inc, as well as clinical trial support from Galapagos NV.

To read the paper
https://www.nature.com/articles/s41434-019-0111-6

http://ccsmonash.blogspot.com/2019/12/ama-victoria-presidents-award-for-prof.html