The U.K. Cystic Fibrosis Trust is partnering with the U.S. Cystic Fibrosis Foundation to fund a Strategic Research Centre (SRC) — a virtual collaboration bringing together investigators with different backgrounds and areas of expertise — to advance the development of gene-editing therapies for treating cystic fibrosis (CF).
“Advancing gene editing therapies is a top priority for the CF Foundation, and it will likely require international collaboration to address fundamental challenges in this area,” William Skach, MD, executive vice president and chief scientific officer of the CF Foundation, said in a report recently published by the CF Trust.
“By working together with the UK Cystic Fibrosis Trust to support this Strategic Research Centre, we are moving one step closer towards our ultimate goal of developing a cure for CF,” Skach said.
In October, the CF Trust committed £750,000 (about $1 million) to fund this SRC, the second to date to focus on gene editing. The first, launched in 2016, supported refinement of the CRISPR/Cas9 gene-editing tool.
“We know that promoting collaboration and developing partnerships is an effective way for us to make the most of our research budget. This has become more important than ever this year as the challenges brought about by the COVID-19 pandemic have meant we’ve had to make cuts to it,” Lucy Allen, director of Research of the CF Trust, said in a press release.
The joint initiative, which is being led by Stephen Hart, PhD, aims to find ways to make gene-editing methods, such as the CRISPR/Cas9 tool, that scientists have been using in cells cultured in the lab to work on complex organs, so that they may be used someday to treat people with CF.
Originally discovered in 1987, CRISPR/Cas9 is a gene-editing tool whose full potential has been recognized only in recent years. This tool can be used to remove, add, or change a portion of the DNA sequence of any gene. For that, it uses a “cut-and-paste” mechanism, in which the enzyme Cas9 is guided toward a specific DNA region of interest with the help of a small guide RNA molecule. RNA and DNA are both nucleic acids, with RNA being produced from DNA.
Researchers working on the SRC will take advantage of this gene-editing tool to develop safer and more effective methods to correct the highest possible number of mutations in the CFTR gene that are known to cause CF.
Unlike other approved therapies for CF, such as Kaftrio (sold as Trikafta in the U.S.), Kalydeco (ivacaftor), and other CFTR modulators that are suitable to treat only a subset of patients carrying specific CFTR mutations, gene-editing therapies have the potential to be used on a more global scale due to their high flexibility.
In lung cells cultured in a lab dish, researchers have shown that gene-editing tools like CRISPR/Cas9 can be used to correct a wide array of CFTR mutations and restore the function of CFTR, the protein that is either absent or malfunctions in CF patients.
Researchers also have demonstrated that once these mutations have been repaired, the transport of water and other molecules in and out of lung cells, which is normally mediated by CFTR, was restored.
Despite their promising therapeutic potential, there are still limitations restricting the use of gene-editing therapies, particularly technical challenges related to scalability and applicability to entire organs, as opposed to single cells. The main goal of the new SRC is to find ways to overcome these challenges.
“We have developed a range of tools and gained a lot of experience in applying gene editing in CF; now we need to refine these and work out the best way to proceed towards therapies for cystic fibrosis,” said Hart, professor of molecular genetics at UCL Great Ormond Street Institute of Child Health in London.
“Making gene editing a reality for people with CF will take the coming together of expertise from across the world. That’s why we’re excited about being able to work in partnership with the CF Foundation to fund our newest, collaborative SRC,” Allen added. “Today there is real optimism that gene editing and other genetic therapies could be a viable treatment option for people with CF in the next decade.”
Of note, Emmanuelle Charpentier, PhD, and Jennifer Doudna, PhD, who developed the CRISPR method of gene editing, won the 2020 Nobel Prize in chemistry.
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