RNAi Therapeutics

Discovery and Development of therapeutic siRNA and microRNA based compounds

Discovery and Development

RNAi (RNA interference) still remains a recently discovered technology leading the fields of diagnostics and therapeutics in genetic research and immunology.  Being one of the greatest scientific achievements within the last decade, RNAi appears to originate from an ancient and widespread genetic immune mechanism. Studies have shown RNAi to play a major role in a cells defense against several types of viruses and is involved in a number of regulatory mechanisms within the cell.

The significance of RNAi is proven by a recent Nobel Prize in physiology being awarded to the research duo of Craig Mello and Andrew Fire for their initial involvement in this field.  Initially, RNAi was viewed as a tool utilized to study particular genes and their related functions by transfecting siRNA into cancer cell lines.  Over a decade’s worth of research in this field has armed scientists with algorithms to predict mRNA targets and methods to quantitate miRNA expression levels such as qRT-PCR, arrays, protein expression levels and RNA-Seq.  The use of siRNA and miRNA synthetic mimics in in vitro transfections or in vivo studies in combination with these methods have resulted in a larger understanding of the role of the RNAi machinery in endogenous gene regulation.

Many scientists recognized the importance of RNAi at its inception, especially its involvement in cancer, but there was intense skepticism in its potential as a therapeutic.  With recent advances, interest in RNAi as a therapeutic active pharmaceutical ingredient (API) is rapidly growing and it is reasonable to expect significant results in the near future.

Therapeutic Application

Understanding that a cell utilizes the RNAi pathway for gene expression regulation, it is plausible that manipulating the RNAi cellular machinery to target viruses or control gene pathways in animals is the next feasible step.  In contrast to small molecule or antibody therapeutic approaches, the driving factor of RNAi therapeutics is the knowledge that miRNAs target multiple genes.  A multi-target therapeutic precludes cells from becoming resistant to treatment by targeting multiple genes in a pathway, unlike single target therapies in which a cell can bypass a single gene in a pathway (e.g. EGFR resistance, etc).

Initial studies utilizing RNAi proved promising results, especially in the realm of viral infection.  In 2002, scientists at MIT stated they had used the RNAi mechanism to inhibit the life cycle of the HIV virus at various stages.  However, rapid mutations in the HIV virus makes it resistant to any therapy, including RNAi.  Broader applications of in vivo RNAi therapy involving human patients is currently under clinical evaluation.

As with any therapeutic, building on the successful results of in vitro studies with in vivo efficacy is a giant hurdle.  The major factor with oligonucleotide therapeutics is the delivery to the target cells, as the delivery of hydrophilic synthetic RNA mimics across a hydrophobic cell membrane remains troublesome.  In order to address delivery issues, the oligo therapeutic can be encapsulated in a lipid nanoparticle, conjugated to an antibody or modified to overcome degradation.  Along with delivery issues, another area to address in oligo therapeutic development is half-life.  Since efficacy is most likely transient, gene silencing through the RNAi pathway needs to be sustained for as long as possible.  By optimizing delivery conditions and adding modifications to limit degradation, the results will be an increase in bioavailability (i.e. amount of circulating drug) which increases the PK/PD effects of the therapeutic.

Therapeutic siRNA development services offered by Altogen Labs located in Austin, TX.

In vivo application enabled by animal siRNA delivery reagents.