Inhalable Cystic Fibrosis Gene Therapy 24 Years In The Making Enters Clinical Trials

The Cystic Fibrosis Foundation estimates that close to 40,000 children and adults are currently living with CF in the United States, which expands to roughly 105,000 people across the world. The outlook for these patients has improved significantly in recent years thanks to the advent of novel treatments. 

The Cystic Fibrosis Trust, using data from the UK Cystic Fibrosis Registry, now estimates that half of people born with CF in 2022 can expect to live to at least 56 years of age. While the condition is life-limiting, this is still a big improvement on the expectations for previous generations, when a large proportion of patients died before reaching adulthood. 

For many patients, relief of their symptoms has been achieved with the help of a class of medications called CFTR modulators. 

Usually, the protein CFTR acts as a channel that helps transport chloride ions in and out of cells throughout the body. In people with CF, both copies of the CFTR gene contain variants that prevent the channel from working correctly. The principal problem this causes, and the root of the symptoms in CF, is that the mucus that is naturally found in various bodily tissues becomes too thick and sticky.

In the lungs, this can cause persistent coughing, wheezing, and frequent infections. In the digestive system, it can affect the absorption of important nutrients and cause issues with bowel function. The symptoms of CF can be very varied. 

CFTR modulators fix the underlying cause of CF by correcting the functioning of the CFTR protein. The first such therapy, ivacaftor, was approved by the US Food and Drug Administration (FDA) in 2012, with three further drugs approved subsequently. In 2019, the first triple combination therapy, marketed under the brand names Trikafta or Kaftrio, was approved by the FDA, targeting a specific CFTR mutation that is thought to be present in 90 percent of CF patients. 

With any treatment, there will always be those who do not respond well, or who may be unable to take it for a variety of medical and non-medical reasons. The more options patients have, the better; hence the new trial of a treatment called BI 3720931.

“We’re breaking new ground in this trial with a gene therapy which has the potential for long-lasting CFTR expression,” said Professor Jane Davies, the UK Lead Investigator for the trial, in a statement. 

This treatment is different because it has the potential to relieve CF symptoms regardless of the underlying genetic mutation, meaning it could be useful for people who don’t benefit from the current CFTR modulators. 

It works by introducing a functioning copy of the CFTR gene directly into the cells lining the airway. The gene is carried inside a lentiviral vector, and the medication is administered via inhalation. 

Lentiviruses work well for gene therapy because they come equipped with the tools needed to insert a gene into a new host cell’s genome. HIV is an example of a lentivirus – its ability to co-opt human cells to manufacture new copies of itself is why it’s such a difficult infection to control. But don’t be alarmed – the lentiviral vectors used in gene therapy are modified to make them harmless. 

This trial has been a number of years in the making; Phase I is the beginning of a long road for any prospective medical treatment, but many will be awaiting the results with anticipation.

“The UK CF Gene Therapy Consortium is very excited to have reached this milestone after 24 years of focused effort and in close collaboration with our funding partners,” commented trial lead Professor Eric Alton, of Imperial College London’s National Heart & Lung Institute. 

“While the immediate target are those patients who are not eligible for CFTR modulators, this novel therapy has the potential to achieve long-lasting CFTR function improvement and disease modification for people with CF irrespective of their mutation type and importantly has the potential for re-dosing if needed.”