Yale scientists use gene editing to correct mutation in cystic fibrosis
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Left to right, cystic fibrosis cells treated with
gene-correcting PNA/DNA show increasing levels of uptake, or use to correct the
mutation. (Images by Rachel Fields)
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The study was published April 27 in Nature
Communications.
Cystic fibrosis is an inherited, life-threatening
disorder that damages the lungs and digestive system. It is most commonly
caused by a mutation in the cystic fibrosis gene known as F508del. The disorder
has no cure, and treatment typically consists of symptom management. Previous
attempts to treat the disease through gene therapy have been unsuccessful.
To correct the mutation, a multidisciplinary team of Yale
researchers developed a novel approach. Led by Dr. Peter Glazer, chair of therapeutic radiology, Mark Saltzman, chair of biomedical engineering, and Dr. Marie Egan, professor of pediatrics and of cellular and
molecular physiology, the collaborative team used synthetic molecules similar
to DNA — called peptide nucleic acids, or PNAs — as well as donor DNA, to edit
the genetic defect.
“What the PNA does is clamp to the DNA close to the mutation, triggering DNA repair and recombination pathways in cells,” Egan explained.
The researchers also developed a method of delivering the
PNA/DNA via microscopic nanoparticles. These tiny particles, which are
billionths of a meter in diameter, are specifically designed to penetrate
targeted cells.
In both human airway cells and mouse nasal cells, the researchers observed corrections in the targeted genes. “The percentage of cells in humans and in mice that we were able to edit was higher than has been previously reported in gene editing technology,” said Egan. They also observed that the therapy had minimal off target, or unintended, effects on treated cells.
While the study findings are significant, much more research is needed to refine the genetic engineering strategy, said Egan. “This is step one in a long process. The technology could be used as a way to fix the basic genetic defect in cystic fibrosis.”
Other Yale authors include Nicole Ali McNeer, Kavitha
Anandalingam, Rachel J. Fields, Christina Caputo, Sascha Kopic, Anisha Gupta,
Elias Quijano, Lee Polikoff, Yong Kong, Raman Bahal, and John P. Geibel.
This research was supported in part by the NIGMS Medical
Scientist Training Program T32GM07205 (to N.A.M.), the Hartwell Foundation (to
M.E.E.) and the National Institute of Health grants R01HL082655 and R01AI112443
(to P.M.G) and R01EB000487 (to W.M.S.).
