US researchers have synthesised a lipid molecule they say shows real promise in gene therapy.
US researchers have synthesised a lipid molecule they say shows real promise in gene therapy. The lipid forms a novel honeycomb complex that the researchers claim is tailored to non-viral DNA delivery.
Most clinical trials in gene therapy use engineered viruses as a vehicle to get therapeutic genes into diseased cells. But these viruses sometimes provoke severe immune responses, prompting researchers to look for alternative gene delivery methods.
The new lipid, synthesised by Kai Ewert’s team at the University of California, Santa Barbara (UCSB), comprises hydrophilic head groups and long, hydrophobic tails. Its DNA delivery potential depends on the molecular complexes formed when positively charged lipids combine with negatively charged DNA.
Ewert’s lipid forms a honeycomb phase (confirmed by X-ray scattering experiments). The tails of the molecules tails gather inside nanoscale cylinders. ’Around these, DNA strands are grouped in an arrangement with honeycomb symmetry through interactions with the lipid’s tree-like head groups,’ Ewert told Chemistry World.
’We’ve been trying to get a lipid-based honeycomb lattice for a long time,’ said Ewert. Researchers at Cyrus Safinya’s lab at UCSB, where Ewert created the new lipid, had previously only seen complexes containing sheets and tubes of lipids. With 16 positive charges in each of its head groups, the new lipid has more than any others currently available in gene delivery: so fewer lipid molecules are needed.
The honeycomb complex comes apart inside the cell because proteins and other negatively charged molecules compete with the DNA to bind the positively charged lipids. The small amounts of lipid needed for drug delivery are not toxic.
Safinya’s team was impressed with the results of testing the new lipid in gene delivery to two human cancer and two mouse cancer cell lines. Ewert said: ’The most surprising result was obtained with the mouse embryonic fibroblast cells known as MEFs.’ The new lipid was 10 times more effective than commercially available lipids for delivering genes to MEFs, which are hard to transfect, he said. The team is now testing the lipid on other cell lines.
K K Ewert et al, J. Am. Chem. Soc., 2006, 206, 3998