Gene editing before birth corrects CFTR mutation in mice: Study
Such an approach could potentially lead to a cure for CF, researchers say
Delivering gene-editing tools to mice while they were still developing in the womb corrected the mutated CFTR gene that causes cystic fibrosis (CF), with the correction lasting into adulthood and restoring normal protein function in the lungs and digestive system, a study found.
While it’s still too early to know if this approach will work in patients, “if we could intervene while the organs are developing, then people would truly be cured of the disease,” Marie Egan, MD, vice chair of research in the department of pediatrics at Yale School of Medicine and a senior study author, said in a university news story.
The study, “Systemic in utero gene editing as a treatment for cystic fibrosis,” was published in PNAS.
Treating disease during pregnancy may offer opportunities
CF is caused by mutations in a single gene called CFTR, which encodes a protein that controls the movement of salt and water in and out of cells. When CFTR is missing or doesn’t work properly, thick mucus builds up, especially in the lungs and digestive system, leading to a range of symptoms.
Organ damage can start before a baby with CF is even born. Egan and other researchers at Yale University believe that treating the disease during pregnancy may offer an opportunity to prevent complications and reduce the need for lifelong therapy.
“If you look at data today, our CF patients are now living into adulthood or even old age,” Egan said. “But the amount of therapy that people take, and the cost, is enormous. If you could actually develop a therapy where you could deliver it once and you wouldn’t have to worry about all this, wouldn’t that be great?”
To correct the mutated CFTR gene in a mouse model of CF, the researchers packaged peptide nucleic acids — lab-made molecules that can attach to a mutated gene, helping cells recognize the mutations and replace it with the correct DNA sequence — inside very small particles called nanoparticles.
“[Peptide nucleic acids] can induce gene editing and are well suited to in vivo applications because they are easily formulated into nanoparticles,” said Peter Glazer, MD, PhD, who chairs the department of therapeutic radiology at Yale School of Medicine and is one of the study’s senior authors.
Single injection corrected CFTR gene mutation in multiple organs
These nanoparticles are designed not only to protect the gene-editing tools, but also help them reach the right cells. When delivered in utero — that is, into the womb of a pregnant mouse — the nanoparticles traveled through the body and reached the developing fetus.
“Our nanoparticles are made of materials that have long proven to be safe in humans,” said Mark Saltzman, PhD, a professor at Yale School of Medicine and Yale School of Engineering and Applied Science, and also one of the senior authors of the study. “Control of their properties is critically important for the successful delivery of the [gene-editing] agents into cells.”
A single in utero injection corrected the mutated CFTR gene in multiple organs, including the lungs and the digestive tract — both of which are commonly affected in CF. CFTR activity was restored to levels similar to those in healthy mice and symptoms were eased into adulthood in some cases. No unwanted changes were observed in other parts of the DNA, suggesting the approach may be safe.
“Gene correction was durable into adulthood in mice, which resulted in functional CFTR activity in both the respiratory and gastrointestinal systems,” the researchers wrote, adding there’s “the possibility that CF could be treated, or possibly cured, by a single in utero [gene-editing] treatment.”
While the approach could be extended to other genetic diseases, “there’s so much for us to learn before that happens,” Egan said. “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.”
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