Delivering Gene Therapy

A TEAM OF ITALIAN RESEARCHERS is opening a route for delivering nucleic acid-based therapies into cells without using potentially problematic viruses as carriers.

Chemists Debora Berti, Piero Baglioni, and colleagues at the University of Florence have created designer phospholipids featuring nucleotide headgroups that can make specific hydrogen bonds to DNA and RNA bases (J. Am. Chem. Soc., DOI: 10.1021/ja0714134). They propose that these phospholipids could be used to get gene therapy payloads into cells.

The system is the first synthetic gene therapy delivery system that employs molecular recognition instead of nonspecific charge interactions to keep nucleic acid-based therapies in their carriers until they reach their destination, Berti says.

"In this era, it is not the finding of the drug that is the main challenge, but delivering it to important intracellular sites," comments Kenneth Dawson, a chemist at University College Dublin, in Ireland.

Currently, the main vehicles for delivering nucleotide-based therapies to clinical-trial patients are viruses, but these can sometimes cause severe immune reactions. Researchers have therefore been looking for alternative strategies for delivering gene-based therapies that are as efficient as viruses. The main alternative is embedding therapeutic DNA or RNA in liposomes, which consist of layers of lipids or polymers and can be engulfed by a cell via endocytosis.

To date, electrostatic attraction between the negatively charged nucleotide payload and positively charged lipid carrier has primarily been used to keep the nucleic acid therapy embedded in liposomes. Unfortunately, the cationic lipids can also bind nonspecifically to anionic serum proteins in blood. Such nonspecific binding decreases the therapeutic payload and can lead to toxicity.

Berti and colleagues' designer lipids feature an anionic nucleotide headgroup that can form hydrogen bonds with uridine, adenine, or thymine nucleotide bases.

"Because these vectors are anionic, they should be able to avoid interactions with problematic serum proteins in in vivo applications," says Cyrus Safinya, a materials scientist at the University of California, Santa Barbara. "These new nucleolipid vectors are a welcome addition to the growing family of novel lipid-based vectors."