In the RNA world hypothesis, RNA based biological life can exist without the need for DNA and proteins to store information, make decisions, and in general, control cells. In 1998, the discovery that small RNAs can play important roles in controlling cells revolutionized biology and perhaps brought us closer to an RNA world.
Since then, the promise that small RNA biology offered for the development of novel biotechnologies is slowly being delivered. Most existing pharmaceuticals function through molecular interactions between drugs or antibodies and their target proteins, but to anyone familiar with biological research labs, RNA interference (RNAi) is a common tool used to reduce expression of proteins in most cell types, including human tissues. Small interfering RNAs (siRNAs) are used to reduce levels of messenger RNA (mRNA) before it has a chance of being translated into protein. RNAi based drugs can therefore, in principle, work like any traditional pharmaceutical against a target molecule.
The design of novel drugs is a difficult process, and here RNA-based pharmaceuticals have one key advantage: siRNAs target genes with similar sequences. This feature simplifies the pharmaceutical design phase and results in active molecules being identified more rapidly for a particular application.
Not surprisingly, siRNA molecules have already appeared in numerous development pipelines. Targets can range from transcripts encoding proteins used by viruses for replication (Alnylam’s ALN-RSV01 interferes with Respiratory Syncytial Virus) to human enzymes that contribute to chronic disease states like high cholesterol levels (Alnylam is also developing molecules to reduce Low Density Cholesterol levels).
However, several debilitating human diseases require more subtle approaches. Instead of simply eliminating offending mRNA, in some cases siRNA-based pharmaceuticals can also alter proteins being produced. This goal requires some more knowledge of the biology surrounding the intended target genes.
In higher organisms like humans, mRNAs encoding protein are usually spliced before being translated to include or exclude portions. This naturally occurring process allows the production of alternative proteins from the same initial mRNA, and siRNAs can be used to control this process. During cell development, it’s been recently reported that large-scale RNA switching occurs in developing muscle cells and that splicing also plays important roles in embryonic stem cell differentiation. RNA splicing was already recognized as a potential target for antisense therapeutics back in 2003 by researchers Peter Sazani and Ryszard Kole at the University of North Carolina.
One of the leading examples of RNA splicing drugs is Isis pharma’s ISIS-SMNRx which is currently going through pre-clinical development as an experimental cure for Spinal Muscular Atrophy (SMA). In SMA, the deletion of a gene eliminates expression of the Survival Motor Neuron (SMN) protein. ISIS-SMNRx can effectively alter the splicing of a similar gene to mimic production of SMN, a technique that has been shown to increase levels of this protein in mice, and may ultimately be able to compensate for the underlying genetic defect in humans.
Development of similar products to control Dystrophin RNA splicing is being pursued by AVI Biopharma as one cure for Duchenne Muscular Dystrophy. AVI acquired Ercole Biotech Inc. in 2008 for approximately $7.5 million, a company developing siRNA switching technology which was co-founded by Ryszard Kole.
The siRNA field is exciting and it’s clear that the biological mechanisms capable of being targeted pharmaceutically are becoming much more complex as science develops. As the technology matures, fundamental processes of stem cell growth being revealed might also be controlled by siRNAs to enhance healing and regeneration, and these discoveries may foreshadow future opportunities in therapeutic settings for ambitious researchers.
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