Abstract: If those of us privileged enough to have the opportunity to work towards curing human diseases had the power to design the ideal therapeutic molecule, the question would be what selection criteria would we choose? Arguably, at the top of the list would be four mandatory properties: specificity, potency, tolerability, and universality. So it should come as no surprise the momentum associated with the field of small interfering RNA (siRNA)-induced RNA Interference (RNAi) therapeutics has gained strength, as these molecules have shown exceptional promise in fulfilling all of these requirements. Unfortunately, siRNAs are too large, too charged, and too rigid to passively diffuse across the cellular membrane and thereby require a delivery system to enter cells. Thus, since its conception of working in human cells, siRNA delivery remains THE 800 Pound Gorilla in the room. The main complication yet to overcome is engineering delivery systems that are safe and efficient in systemically delivering siRNA molecules to the diseased tissue and across the cellular membrane of target cells. Currently, encapsulating the siRNA in nanoparticle and liposomal systems has risen to become the standard of delivery approaches. While generally speaking these delivery platforms offer significant advancements, our laboratory is committed to generating alternative siRNA delivery technologies that avoid nanoparticle packaging and allow siRNA molecules to be delivered as single, soluble entities. This brief review discusses the first of these technologies, a Peptide Transduction Domain-dsRNA Binding Domain (PTD-DRBD) fusion protein that avidly binds to the siRNA backbone to mask the negative charge and uses the PTD for macromolecular cellular delivery. ... Read more

Antisense technology is based on the principle that antisense oligonucleotides (AO) can specifically alter gene expression and the pattern of splicing at the RNA level. The first application of such technology 25 years ago was for knockdown of targeted viral gene expression (Zamecnik et al., 1978), which was achieved by targeting mRNA with AO to block the viral gene translation or induce its degradation. Such strategies have now been developed as powerful tools for the functional analysis of targeted genes in the laboratory and are suggested to be of great therapeutic potential against diseases from viral infections to cancers. More ... Read more

The antisense oligonucleotide method, in which a short segment of nucleotide sequence matching with a specific mRNA is introduced into cells to quench the mRNA’s translation into protein, is a powerful biotechnology. From a practical point of view, C.A. Stein from Columbia University critiqued the current misuse of the technology and inappropriate interpretation of experimental results, and also gave empirical advice on how to avoid some common pitfalls (J. Clin. Invest. 108:641).

Phosphorothioate oligonucleotide is chosen for its stability. Currently, maximum specificity of oligonucleotides is achieved by those at a length of 16-20 bases. Important advice include:

More antisense oligo sequences should ... Read more

Isis and Eli Lilly announced that Isis Pharmaceuticals (Carsbad, California) will receive a $200 million deal from Lilly for an agreement that Lilly will have the marketing rights to a promising antisense drug that is in phase III clinical trial testing by Isis. The drug, Isis 3521, is an antisense inhibitor of the protein kinase C-alpha gene for treating non-small cell lung cancer. The $200 million deal comprises of an immediate cash payment, milestone cash payment, interest-free loan, and equity investment.

Isis has come a long way to savor its success. Its first generation antisense drugs were largely unsuccessful. Isis has ... Read more