New gene therapy improves vision in blind mice
Sahay and graduate student Siddharth Patel, first author on the study, found that phytosterols - plant-based molecules chemically similar to cholesterol - change the shape of the nanoparticles from spherical to polyhedral and cause them move faster.
That's important because once inside a cell, the nanoparticles need maneuverability for the escape they need to make: from a cell compartment known as an endosome into the cytosol, where the delivered genes can perform their intended function.
One of the biggest challenges in the delivery of genes is that less than 2% of the nanoparticles reach the cytosol. If you up the dose to get more genes there, now you have problems with toxicity, plus the cost goes higher. But the nanoparticles' shape changes because of these naturally occurring cholesterol analogs, and the new shape helps them deliver genes better. The analogs boost gene delivery 10-fold and sometimes 200-fold." Gaurav Sahay, assistant professor of pharmaceutical sciences in the OSU College of Pharmacy
The finding can be used to make inhalable particles that can cross several barriers in the lung in a cystic fibrosis patient, enabling patients to be treated with much higher efficacy , Sahay added.
"In this latest research, we hypothesized that with the analog inclusions, there would be shape changes and changes with how the nanoparticles interact with the cell and how the cell perceives them," Patel said. "For instance, the sterols might help them get to the ribosomes for translation faster. This opens up a whole new area of research - the shape and structure and composition of the liquid nanoparticles now become quite relevant. We're just scratching the surface on the way to building LNPs with a rational design to get different properties for treating different diseases with cell-type specificity."
Scientists at Duke University and Moderna Therapeutics, a Massachusetts-based biotech firm that is a leader in mRNA-based gene therapy, also collaborated on the study.
The National Heart, Lung and Blood Institute, the National Institute of Biomedical Imaging and Bioengineering, the Cystic Fibrosis Foundation, Moderna Therapeutics and the College of Pharmacy supported the research.
The Cystic Fibrosis Foundation has awarded Sahay an additional $800,000 to continue this work, pushing him past the $4.5 million mark in funding from all sources to study cystic fibrosis therapies. Source:
Oregon State University Journal reference:
Patel, S., et al. (2020) Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA. Nature Communications . doi.org/10.1038/s41467-020-14527-2 .
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