In vivo correction of cystic fibrosis mediated by PNA nanoparticles

Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We sought to correct the multiple organ dysfunction of the F508del CF-causing mutation using systemic delivery of peptide nucleic acid gene editing technology mediated by biocompatible polymeric nanoparticles. We confirmed phenotypic and genotypic modification in vitro in primary nasal epithelial cells from F508del mice grown at air-liquid interface and in vivo in F508del mice following intravenous delivery. In vivo treatment resulted in a partial gain of CFTR function in epithelia as measured by in situ potential differences and Ussing chamber assays and correction of CFTR in both airway and GI tissues with no off-target effects above background. Our studies demonstrate that systemic gene editing is possible, and more specifically that intravenous delivery of PNA NPs designed to correct CF-causing mutations is a viable option to ameliorate CF in multiple affected organs.

Cystic fibrosis and fat malabsorption: Pathophysiology of the cystic fibrosis gastrointestinal tract and the impact of highly effective CFTR modulator therapy

“…Current recommendations suggest the use of general population dietary guidelines for fat to provide 20%–30% of total caloric intake for adults, increasing to 35%–40% of calories for children or for adults with undernutrition 209 . General nutrition recommendations for pwCF should stress the importance of consuming an age‐appropriate healthy diet, modified as needed to maintain optimal nutrition status at each step of the life cycle 209,210 . Individualization of nutrition management for each pwCF is emphasized.…”

Recent progress in nanomedicine-mediated cytosolic delivery

“…These non-viral vehicles can have non-targeted and uncontrolled genetic alterations. 64 Depending on the composition of the cell membrane, membrane proteins and cholesterol can alter the intracellular delivery mechanisms of nanomedicines. Given that complexity and heterogeneity, NP surfaces have to be developed accurately to maximize their cytosolic delivery potential.…”

Engineered Plant Virus Complexes with a RANK Motif Modulator and Bone Targeting for Osteoporosis Treatment

“…In recent years, biomaterials have offered an excellent platform for drug delivery. − Lipid-based nanoparticles, polymeric nanoparticles, and inorganic nanoparticles are among the main categories of nanomaterials that have been developed. − With the pandemic of COVID-19 and the development of related vaccines, viral vector and virus-like nanoparticles (VNPs) have attracted worldwide attention as a result of properties including high stability, good loading capacity, simple assembly, and easy modification. − The plant VNPs obtained from cowpea chlorotic mottle viruses (CCMVs) are sphere-like icosahedra of about 28 nm in diameter . Notably, interaction studies have proven the safety and non-infection of plant viruses and virus-like particles in mammals .…”