The Promise of miRNA Therapeutics
Expression and functional studies suggest that the altered expression of specific miRNAs is critical to a variety of human diseases. Mounting evidence indicates that the introduction of specific miRNAs into disease cells and tissues induces favorable therapeutic responses. The promise of miRNA therapy is perhaps greatest in cancer due to the apparent role of miRNAs as tumor suppressors. The rationale for miRNA-based therapeutics for cancer is supported by the following observations:
- miRNAs are frequently mis-regulated and expressed at altered levels in diseased tissues when compared to normal tissues. Numerous laboratories have provided strong evidence showing that miRNAs are consistently altered in cancerous tissues relative to their corresponding normal tissues. Often, altered expression is the consequence of genetic mutations that lead to increased or reduced expression of particular miRNAs. Various diseases reveal unique miRNA expression signatures that can be exploited as diagnostic and prognostic markers. Mirna Therapeutics (while Asuragen) has generated a large collection of data describing miRNAs with differential expression in normal and tumor tissues.
- Mis-regulated miRNAs contribute to cancer development by functioning as oncogenes or tumor suppressors. Oncogenes are defined as genes whose over-expression or inappropriate activation leads to oncogenesis. Tumor suppressors are genes that are required to keep cells from being cancerous; the down-regulation or inactivation of tumor suppressors is a common inducer of cancer. Both types of genes represent preferred drug targets to specifically target the molecular basis for a particular cancer. Examples of oncogenic miRNAs are miR-155 and miR-17-92; let-7 is an example of a tumor suppressive miRNA. Mirna Therapeutics has established a proprietary portfolio of miRNAs that meet these criteria.
- Administration of miRNA induces a therapeutic response by blocking or reducing tumor growth in pre-clinical animal studies. The scientific literature provides proof-of-concept studies demonstrating that restoring miRNA function can prevent or reduce the growth of cancer cells in vitro and also in animal models. A well-characterized example is the anti-tumor activity of let-7 in models for breast and lung cancer. Mirna Therapeutics has an active research program to evaluate the therapeutic potential of miRNAs and has identified lead candidates that reduce the tumor burden in several pre-clinical animal models.
- A given miRNA controls multiple cellular pathways and therefore may have superior therapeutic activity. Based on their biology, miRNAs function as “master switches” of the genome, regulating multiple gene products and coordinating multiple pathways. Genes regulated by miRNAs include genes that encode conventional oncogenes and tumor suppressors, many of which are individually pursued as drug targets by the pharmaceutical industry. Thus, miRNA therapeutics may have superior activity by targeting multiple cancer-associated genes. Given the observation that mis-regulation of miRNAs is frequently an early event in the process of tumorigenesis, miRNA therapeutics, which replace missing miRNAs, may be the most appropriate therapy.
- miRNAs are natural molecules and are therefore less prone to induce non-specific side-effects. Millions of years of evolution helped to develop the regulatory network of miRNAs, fine-tuning the interaction of miRNA with target messenger RNAs. Therefore, miRNAs and miRNA derivatives will have few if any sequence-specific “off-target” effects when applied in the proper context.
Delivering on the Promise of miRNA Therapeutics
Similar to siRNAs and other oligonucleotide-based drugs, miRNAs do not freely diffuse into cells and thus require assistance to enter diseased cells. Therapeutic applications of miRNAs will benefit significantly from the on-going efforts of a variety of companies that are developing technologies that facilitate the delivery of therapeutic siRNAs.
The physical characteristics of siRNAs and miRNAs are similar. Mirna scientists have found that technologies that are effective in delivering siRNAs are likewise effective in delivering synthetic miRNAs. Mirna has numerous collaborations with both academic and industrial groups that have developed methods for systemic oligonucleotide delivery. We encourage interested parties to contact us at info@mirnatherapeutics.com.