Gene editing targeting lungs shows promise in preclinical study

Therapy's developer working on other genetic medicines for CF

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A lung-targeted gene-editing therapy designed using technology from ReCode Therapeutics was able to successfully correct a disease-causing CFTR gene mutation in lung cells derived from cystic fibrosis (CF) patients, according to a recent proof-of-concept study.

The therapy, developed using ReCode’s Selective Organ Targeting (SORT) lipid nanoparticles (LNPs), was able to specifically target lung stem cells of mice when delivered systemically via an intravenous (into-the-vein) infusion.

“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,” Marco Weinberg, PhD, head of research at ReCode, said in a company press release.

The study, “In vivo editing of lung stem cells for durable gene correction in mice,” was published in Science.

The symptoms of CF are caused by mutations in the CFTR gene that encodes production of the CFTR protein, which is important for regulating the balance of salt and water in cells. Consequently, the CFTR protein is faulty or deficient, and the body’s mucus becomes overly thick and salty.

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RCT2100 designed to provide patients with healthy CFTR mRNA

ReCode is working on developing genetic medicines for CF that work in various ways to enable the body to produce more healthy CFTR protein. Its lead candidate, called RCT2100, is designed to provide patients with healthy CFTR mRNA a template molecule used when translating the information from DNA into a protein.

The company is also teaming up with Intellia Therapeutics to design gene-editing therapies that would correct the deficit in the patient’s own gene.

These genetic medicine candidates are all packed into lipid nanoparticles, or LNPs, that help them to be taken up by cells. While first-generation LNPs are largely taken up by the liver, the SORT LNP platform designs them in ways that allow them to be targeted to specific organs other than the liver.

In CF, where thick and sticky mucus accumulates in the lungs, ReCode is aiming for lung-targeted therapies. By engineering the LNPs to go specifically where they’re needed, it also enables multiple different modes of administration to be used. For example, even if a medicine is infused into the bloodstream, it should still be able to make its way to lung cells.

Another goal of genetic medicines is for them to be taken up by stem cells in the target tissue. These versatile cells give rise to virtually all other mature cell types in the body. Correcting the genetic deficit in stem cells means that all their progeny cells also will have the correction, providing more durable treatment responses.

The recent study provided proof-of-concept evidence that lung-targeted LNPs developed using ReCode’s SORT platform could achieve lung stem cell editing when delivered into the bloodstream.

Results showed that such a therapy enabled editing of more than 70% of stem cells in the lungs of mice when delivered intravenously. More than 80% of mature lung epithelial cells — a major lung cell type — showed signs of the gene editing that were sustained for up to 660 days, or about 1.8 years.

The scientists then tested whether a lung-targeted genetic medicine could correct a CF-causing mutation that is not treatable with available CFTR modulator therapies such as Trikafta (elexacaftor/tezacaftor/ivacaftor), called R553X.

In cells from CF patients with the mutation, the treatment corrected the genetic defect by more than 95% and restored CFTR protein function similar to what is observed with Trikafta in people with an eligible mutation. It also corrected the mutation in more than 50% of lung stem cells in a mouse CF model.

The findings support ReCode’s ongoing research into translating their gene correction approach into clinical settings, which the company indicates will require additional safety studies in larger animals before moving into clinical trials.

Meanwhile, RCT2100 is currently being tested in a Phase 1 clinical trial involving healthy volunteers with plans to move forward with testing in CF patients. The inhaled medication is particularly intended for CF patients with Class 1 CFTR mutations, who are generally ineligible for CFTR modulator therapy.