Dear Editor:

 

We read with interest your commentary on the comparison between antisense and siRNA approaches to target messenger RNA recently published in the Proceedings of the National Academy of Sciences. (See BioWorld Today, Sept. 22, 2008.) We certainly agree that the merit of siRNA as a technology with potential drug candidate properties still needs to be demonstrated.

Care should be taken in that the article referred to post-transcriptional gene silencing (PTGS) as a global term for disrupting the cell's ability to use mRNA and not antisense DNA. Further, the use of PTGS for therapeutic purpose might better be termed RNA-based therapeutics. To this end, inclusion of chemistries (phosphorodiamidate morpholino oligomers [PMO], peptide nucleic acids [PNA], etc.) that do not require cellular cofactors (RNAse H and RISC) deserve to be included in the efficacy, specificity and therapeutic potential comparison.

One notes that the effects of siRNA termed in vivo in the Rudnick paper were in fact in cell culture. Thus, the observations are far removed from the issues of drug delivery in animals and patients. The key requirements for ultimate human use will remain stability or resistance to nucleases, efficient distribution to target tissues and sufficient residence time to provide for accumulation of effective tissue concentrations.

Animal challenge models involving both siRNA and PMO chemistries as antiviral agents for Ebola virus and respiratory syncytial virus (RSV) have been described in the literature. In both cases the PMO was equal to or superior to the siRNA approach in reducing viral titer or promoting survival. A critical difference has been the use of lipid encapsulation for the siRNA where the PMO has been injected as a sterile solution. The simple PMO approach to Ebola was successful in mouse, guinea pig and monkey lethal challenge models, which represents the most advanced progress toward a human drug to date for this pathogen.

We would also like to bring to your attention a series of publications related to treatment of Duchenne muscular dystrophy in the mouse model of the disease. These mice fail to produce essential protein, dystrophin, because of a mutation in the dystrophin gene. In these reports modified peptide-conjugated morpholino antisense oligomers restored production of dystrophin by altering splicing of dystrophin messenger RNA and had significant therapeutic effects in the treated mice. This approach to RNA-based therapeutics has not been addressed by siRNAs, mostly due to the inherent limitations of siRNA's mechanism of action, but represents a significant advancement in the approach to treating genetic diseases.

To achieve successful RNA-based therapeutics, the industry requires the most innovative approaches to attain bioavailability and drug-like character. SiRNA cannot, in principle, provide the total solution as the technology operates solely be degrading the target mRNA. Success in RNA-based therapeutics will not come by an inflexible adherence to one technology platform or another. Pragmatism will determine the winners and losers.

 

Ryszard Kole

Patrick L Iversen

 

AVI BioPharma

Corvallis, Ore.

 

References:

Warfield et al., (2006) PLoS Pathogens 2(1):e1

Lai et al., (2008) Mol Ther 16:1120-1128 [note: front page review by BioWorld]

Jearawiriyapaisarn et al., (2008) Mol Ther 16:1624-1629

Yin et al., (2008) Hum Mol Genet Sept 10. [Epub ahead of print]

Wu et al., (2008) Proc Natl Acad Sci USA 105:14814-14819