When it comes to challenges in the genome editing space, all eyes are on delivery. Efficient editing of cells directly in an organism (rather than ex vivo) and targeting of relevant stem cells is still a hurdle to be cleared in the progress of genetic medicine.
Now, new work describes the optimization of lipid nanoparticles (LNPs) for delivering gene-editing reagents and delivery to all lung cell types, including stem cells. The approach, which was tested in patient-derived cells and in a mouse model of cystic fibrosis, demonstrated therapeutically relevant editing lasting for up to a year.
The work is published in Science in an article titled, “In vivo editing of lung stem cells for durable gene correction in mice.” The research describes the ability of Selective Organ Targeting (SORT) LNPs to facilitate high levels of persistent gene editing in lung stem cells when given systemically via intravenous injection. The work was a collaboration between researchers at the University of Texas Southwestern Medical Center, Dallas, and ReCode Therapeutics, in Menlo Park, CA.
Daniel Siegwart, PhD, associate professor in the Department of Biochemistry and the Simmons Comprehensive Cancer Center (SCCC) at UT Southwestern Medical Center and co-founder of ReCode Therapeutics, led the effort to develop SORT LNPs that could efficiently deliver gene-editing tools away from the liver and directly to cells in the lung.
This is the first study to show that LNPs carrying gene editing tools can effectively correct a gene in lung stem cells when administered intravenously and delivered through systemic circulation. This approach enabled over 70% editing efficiency in mouse lung stem cells, sustaining the effect for up to 660 days, a result which, if translated into the clinic, may offer the potential for sustained benefits for patients with genetic lung diseases.
Proof of concept was demonstrated for correction of the cystic fibrosis (CF) mutation CFTR R553X, which is untreatable with currently available small molecule therapies. The new technique restored CFTR protein function in cells derived from CF patients, potentially offering a path for a durable treatment for CF.
More specifically, “NG-ABE8e messenger RNA (mRNA)–sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice.”
“Achieving long-lasting gene correction in lung stem cells highlights the growing potential of SORT LNPs to deliver effective treatments for conditions like cystic fibrosis and could pave the way for our technology to advance durable therapies for other genetic diseases,” said Marco Weinberg, PhD, head of research at ReCode.
ReCode’s lead programs include RCT1100 for the treatment of primary ciliary dyskinesia caused by pathogenic mutations in the DNAI1 gene, and RCT2100 for the treatment of the 10–13% of cystic fibrosis patients who have Class I mutations in the CFTR gene and do not respond to currently approved CFTR modulators. RCT1100 and RCT2100 are inhaled disease-modifying mRNA-based therapies formulated using the SORT LNP delivery platform.
Further studies are needed to explore the mechanisms underlying efficient delivery to airway stem cells, assess safety and tolerability in larger animals, and evaluate efficacy in human trials.