A research team from Yale University developed a new strategy to correct the most frequent mutation that causes cystic fibrosis. The study entitled “Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium” was published in Nature Communications by Nicole Ali McNeer and Kavitha Anandalingam, co-first authors, and Marie Egan, senior author, from Yale University along with colleagues.
Cystic fibrosis (CF) is a hereditary, fatal disease that affects the lungs and digestive system, most frequently caused by a mutation in the cystic fibrosis gene known as F508del. There is no cure for this condition and the standard therapy is to control the symptoms. Unfortunately, efforts to treat this condition have failed. Cystic fibrosis is still not suitable for gene therapy due to its systemic nature and challenges including in vivo gene delivery and transient gene expression.
In this study, the research team used synthetic molecules similar to DNA designated by peptide nucleic acids (PNAs) as well as donor DNA in biodegradable polymer nanoparticles to correct F508del. Moreover, they developed a strategy to deliver the PNA/DNA using microscopic nanoparticles. These very small particles with a dimension of billionths of a meter in diameter are precisely designed to enter the target cells. To test this strategy, the authors used human airway and mouse nasal cells as well as a mouse model. They performed intranasal delivery of nanoparticles in CF mice. This strategy produced changes in the nasal epithelium of the mice as well as correction of the targeted genes in the nasal and lung tissues that were consistent with corrected CFTR function. Importantly, they observed minimal off target effects on treated cells.
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“What the PNA does is clamp to the DNA close to the mutation, triggering DNA repair and recombination pathways in cells,” said Dr. Egan in a news release.
Dr. Egan said that these findings are very important but there is the need to optimize the genetic engineering strategy. “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,” concluded Dr. Egan.