In utero genome editing treats cystic fibrosis in mice

Genome editing administered to fetal mice has corrected the mutation causing cystic fibrosis before birth.

Researchers at Yale School of Medicine in New Haven, Connecticut, have demonstrated a method that corrects the causative mutation in cystic fibrosis by in-utero administration of a gene therapy. Using this method, they were able to restore the activity of the affected gene to levels similar to those of normal mice.

'Our [cystic fibrosis] patients are now living into adulthood or even old age... but the amount of therapy that people take, and the cost, is enormous,' said Professor Marie Egan co-senior author of the study published in PNAS. 'If we could intervene while the organs are developing, then people would truly be cured of the disease.'

Cystic fibrosis is a genetic condition that affects multiple organs due to a common mutation in the CFTR gene. This includes the respiratory, gastrointestinal, and reproductive systems; with the harmful pathology presenting at birth.

Treatment for cystic fibrosis has improved over the years, especially with the use of CFTR modulators – drugs that restore protein function – but these require repeated administration. Therefore, the researchers are hoping to create a genome editing approach that could correct the mutation in fetal life.

The researchers used synthetic DNA molecules known as peptide nucleic acids (PNAs), which can bind DNA sequences and correct them. These were delivered into the wombs of pregnant mice using lipid nanoparticles.

'PNAs can induce gene editing and are well suited to in vivo applications because they are easily formulated into nanoparticles,' said Professor Peter Glazer, a senior corresponding author of the study.

The newborn mice were tested after four and eight months to see if their genomes had been successfully edited. The researchers observed significant improvements across multiple organs, with no off-target effects.

The researchers say that this study could potentially lead to a single-use genome editing treatment for cystic fibrosis. However, they stress that more work is required to translate these findings before a clinical trial could take place in humans.

'There's so much for us to learn before that happens,' said Professor Egan. 'But I do think this is an incredible time, and we are seeing gene editing therapies in the clinic now. There are definitely some diseases where this approach has made a huge difference in the outcomes of children.'