Trojan horse: RNAi liposomes silence EGFR function (right). Credit: W. PARDRIDGE/UCLA

At the University of California, Los Angeles, professor of medicine William Pardridge has developed a ‘molecular Trojan horse’ strategy for RNA interference (RNAi) delivery, which is licensed to drug-delivery specialists ArmaGen Technologies in Santa Monica, California. It consists of incorporating either peptides or monoclonal antibodies that target membrane-bound receptors into 85-nanometre-diameter liposomes containing plasmid DNA with the desired siRNA sequence. The lipids are coupled to polyethylene glycol to prevent nonspecific fusion with the cell membranes of non-target cells. This strategy aims both to protect the DNA from degradation by nucleases and to ensure its sequential uptake by endocytosis across the blood–brain barrier and the cell and nuclear membranes of neurons. The system has been tested in adult mice and rhesus monkeys, and Pardridge hopes to see it in clinical trials against brain cancer “within two years”.

Trojan horses also feature in TargeTran, the delivery system from Intradigm in Rockville, Maryland. TargeTran involves nanoparticles formed by the self-assembly of positively charged polymers with the negatively charged siRNA, encasing and protecting it. Additional ligands are added for targeting to particular tissues after intravenous injection, and combinations of siRNAs can be used to inhibit multiple drug targets.

One of Intradigm's targets is the vascular endothelial growth factor (VEGF) pathway, which is involved in angiogenesis in tumours and other diseases. Martin Woodle, chief scientific officer at Intradigm, hopes to take the VEGF-targeting technology into the clinic, first for cancer next year, and then against age-related macular degeneration, a relatively common cause of blindness, which involves abnormal blood vessel growth in the retina. Alnylam, of Cambridge, Massachusetts, is also developing siRNA therapeutics against this condition.

But Woodle's collaborator Raymond Schiffelers at the Netherlands Cancer Institute in Amsterdam cautions that many ligands targeting multiple receptors are likely to be needed for the clinical application of RNAi against cancer, which in humans “will be far more complex because there are different phases of tumorigenesis where parts of the process are not angiogenic”. Intradigm is also collaborating with researchers in Guang Zhou, Hong Kong and Beijing to produce RNAi-based therapy against the coronavirus that causes severe acute respiratory syndrome (SARS).

JULIE CLAYTON