New Breakthrough in the Systemic Delivery of RNAi for the Brain

One often cited challenge for the wide application of RNAi in the treatment of disease is the systemic delivery of the RNAi inducing agent to the appropriate target cells. Systemic delivery is the ability to deliver RNAi to target cells following intravenous or even oral administration, whereas local, also called “Direct RNAi” approaches for eye, lung, and mucosal diseases appear to be less of a challenge.

Neurodegenerative diseases and other brain-related diseases are an attractive area for the application of an RNAi therapeutic, due to significant unmet medical needs and the existence of well validated gene targets. The delivery of RNAi to the CNS, however, is challenging due to the presence of the blood-brain barried (BBB) which makes it difficult for macromolecules to exit blood vessels and enter the CNS. First generation RNAi therapeutics for the CNS may therefore rely on direct injection or device implantation as is illustrated by the current Alnylam-Medtronic collaboration. Systemic delivery, however, would have the added advantage that a therapeutic would be well distributed throughout the brain due to the extensive vascularisation of the brain. Local administration strategies often suffer from the fact that the therapeutic agent is restricted to the site of application.

The paper published this Monday online in the leading scientific journal Nature by Kumar et al. shows that the ability of the rabies virus to cross the BBB can be conferred onto an siRNA if it was non-covalently linked to a 29 amino acid peptide from the rabies virus. Although the mechanism by which this peptide achieves this is unclear, the authors show that once in the CNS it binds to acetylcholine-receptors on neuronal cells and concomitantly delivers the siRNA load to those cells. A number of endogenously expressed genes were thereby targeted achieving 30-70% knockdown efficiencies, including a 70% reduction in SOD-1 activity.

SOD-1 when mutated is linked to the debilitating neuronal disease ALS (Amyotrophic Lateral Sclerosis; aka Lou Gehrig’s) for which there is no real treatment. Interestingly, preclinical therapeutic effects have previously been achieved with lentivirally delivered shRNAs. It is therefore hoped that ultimately RNAi may offer the first treatment alternative for ALS that addresses the underlying cause of the disease.

In another impressive demonstration of the system, almost all mice infected with an otherwise fatal dose of Japanese Encephalitis Virus were rescued when they received the rabies-peptide siRNA combination. This follows a report last year by the same group that single siRNAs could also protect against the related West Nile Virus.

This report demonstrates that progress in the delivery of RNAi Therapeutics can come from unexpected sources and illustrates the force and commitment with which this technology is moving forward. It is reasonable to assume that one by one, similar solutions and improvements to the RNAi delivery challenge will come for other difficult-to-target tissues. Further improvements to the present system should also be possible, as the authors suggest, for example through covalent conjugation of the siRNA to the peptide to avoid premature dissociation of the siRNA from the rabies peptide. It is also tempting to imagine that high-throughput approaches such as one involving peptide phage display libraries could yield siRNA-peptide combinations for other tissues of the body.

The key will be that the results can be reproduced in another laboratory, is easy-to-use, and similarly non-immunogenic in man as it is in mice. In that case, I would not be surprised to see the technology being licensed by a major RNAi Therapeutics company. The proximity of Harvard to Alnylam’s Cambridge, Mass., headquarters certainly makes this company a prime candidate for that. It should also be noted that one of the co-authors, Beverly Davidson from the University of Iowa, an acknowledged RNAi expert with experience in brain-related RNAi applications, had been associated with Sirna Therapeutics prior to their acquisition by Merck.