We're trying to cure Cystic Fibrosis - will you join us?

There is an unfounded belief often suggested by commentators that recent advancements in modulator therapies have rendered cystic fibrosis (CF) manageable for all patients. While recent advancements in modulator therapies have made cystic fibrosis manageable for many people, there are still thousands globally who still suffer from this debilitating disease. We cannot make the assumption that ‘we are done with CF’.

At Deep Science Ventures, we are collaborating with the Cystic Fibrosis Foundation to create ventures aimed at solving the underlying causes of CF and helping propel us towards a world where the disease can truly be put behind us. To aid us in our journey, we are actively recruiting entrepreneurial scientists to join us in this endeavour.

Living with CF

CF is a rare, inherited disease, which tends to worsen over time and can often lead to fatal complications. 

In the 1950’s, children with CF rarely lived long enough to attend elementary school. Today, thanks to advancements in treatments and therapeutics, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators, anti-infectives, and mucus-thinning drugs, people with CF are living longer and fuller lives. Around half the people born today with CF will live past the age of 50 [Ref]. And while the disease never quite recedes into the background, it does not prevent people from pursuing their hopes and dreams, going to school, forming families, and getting jobs. 

Our vision is to amplify those possibilities even further, by shining a light on the roots of the disease and gradually reducing its hold on people’s lives.  

Causes and Prevalence of Cystic Fibrosis

CF affects approximately 1 in 2,500 people. Roughly 70,000 people have CF globally with ~14% of these in the UK.

CF can be caused by one of more than 2,000 different mutations that have been found in CFTR, an ion channel. These mutations cause the protein to not function properly, because it’s misfolded, shortened, or doesn’t work properly when it gets to the membrane. This mutated protein is present throughout the whole body and most notably causes the disruptive build-up of thick mucus found in the lung. 

Those mutations are broadly categorised across five classes: protein production, protein processing, gating, conduction, and insufficient protein. The way those mutations are categorised, studied and understood has important implications for the types of treatments that have been developed and pioneered over time. 

Existing Treatments and Limitations

In the last decade, a number of drugs have been developed by Vertex Pharmaceuticals that help to support and improve the function of the faulty transport protein. The first of these, ivacaftor (sold as Kalydeco), helps increase the flow of ions through the channel, but only works in patients with CFTR mutations in which CFTR gets to the cell membrane, but doesn’t function properly once it’s there (~5% of people with CF). 

Combination therapies, in which ivacaftor is added to drugs – such as tezacaftor, lumacaftor, and elexacaftor – that prevent CFTR from misfolding en route to the membrane, can be used to treat nearly 90% of people with CF. The premise of the triple therapy (elexacaftor/tezacaftor/ivacaftor), sold as Kaftrio (Trikafta in the United States) is that it utilises three drugs that each perform different roles and jointly impact the production or function of the CFTR protein. It therefore aims to address the underlying causes of the disease as well as alleviate its symptoms.

Kaftrio has been shown through clinical trials to provide people with two copies of the F508del mutation a 10% increase in lung function when compared to being treated with Symkevi, another medicine. The benefit was even greater for people with a single copy of F508del who had more than a 14% increase in lung function compared to the placebo treatment. [Ref]

The drug has been available in England since August 2020 in what was hailed at the time as a landmark deal for the NHS. Kaftrio is thought to cost around £100k per patient per year, after negotiations with Vertex. [Ref

However, while Kaftrio and other drugs are a significant improvement on what was previously available, there are still limitations:

- Drugs that target faulty proteins will never work for the ~10% of CF patients that do not express the protein at all 

- Some patients have adverse reactions to these drugs

- Patients taking these drugs need routine monitoring for potential liver toxicity and the development of cataracts, both of which have been observed (albeit rarely)

- These drugs are not cures and patients must still manage their symptoms.

A Systemic, Multi-Organ Approach to Curative Therapeutics in CF

There is an additional issue at play here: the modern-day focus is primarily on CF as a lung disease. Over 90% of CF patients die from lung-related complications, which also helps explain why, in the later stages of the disease, people with CF may require lung transplantation [Ref].

The lung complications have influenced the way that CF research is conducted. Whether the aim is to clear the obstructive mucus, correct the genetic mutation itself (through gene supplementation or editing), or help this faulty transport protein function, the focus remains on the lung. This manifests in extensive research being conducted to further our understanding of cystic fibrosis in the lungs: of the CF publications on gene therapies, one potential curative strategy, the lungs are mentioned 14X and 20X more often than the pancreas and gastrointestinal tract, respectively. 

We believe we must broaden our approach beyond focusing solely on the lung.  

CF is caused by mutations in a single gene, so genetic therapies have the potential to be curative. Although gene therapies have been developed in the past, most of these were administered by inhalation, which may not be the most effective route. In addition, inhaled therapies would only improve lung function, not the function of other affected organs. An approach that delivers an intact copy of the gene encoding CFTR to multiple organs could provide a durable cure. 

To achieve that we are exploring different delivery strategies that have been shown to naturally reach these hard-to-reach tissues and re-engineering them to overcome the issues specific to CF.

We believe that this multi-organ, systemic approach to cystic fibrosis research and drug development is needed in order to generate potential curative therapeutics strategies.

Delivering Patient Outcomes Through Venture Creation

This systemic approach is novel and comes from the type of thinking that has been applied in other areas of focus at Deep Science Ventures. Last year DSV developed 3 out of 4 of CRUK’s spinout companies: Enedra, Neobe and Stratosvir. In each of these companies, we used our systematic approach to identify the most promising strategies within a given area. Research is led by a Founding Analyst who then goes on to become a Co-Founder in the venture, alongside a complementary team.

We are looking to use this approach to develop curative therapeutics for CF. Alongside the experienced team of PhDs and exited-Founders at DSV who work alongside the Founding Analyst, we have world-leading collaborators in the Cystic Fibrosis Foundation, DSV’s advisory board, and our network of company builders and investors. Are you a gene delivery or cystic fibrosis expert, looking to help us deliver that change? If so, please get in touch with us here.