miRNA Replacement Therapy

There are two main therapeutic strategies related to miRNAs. miRNAs that acquire a gain-of-function in the diseased tissue (e.g. oncogenic miRNAs) can be inhibited by using miRNA antagonists, such as anti-miRs and antagomiRs. miRNAs that show a loss-of-function (e.g. tumor suppressor miRNAs) can be restored by using miRNA mimics.

Mirna Therapeutics, Inc. is pursuing the ”mimic” strategy or what we refer to as “miRNA Replacement Therapy”. Thus, tumor suppressor miRNAs that show a loss of function in cancer can be “replaced” by therapy involving the re-introduction of miRNAs into diseased tissues, reactivating pathways that drive a therapeutic response. In many cases, reactivation of these miRNA-regulated pathways interferes with the oncogenic properties of cancer cells, blocking uncontrolled proliferation and inducing the apoptotic cascade. Thus, miRNA replacement is distinguished from the miRNA antagonism strategy pursued by most other companies and is highlighted by the following scientific observations:

  • The majority of aberrantly expressed miRNAs is expressed at reduced levels, suggesting that miRNAs as a whole function as tumor suppressors. This hypothesis is supported by the fact that inhibition of the general processing of endogenous miRNAs induces oncogenic cellular transformation (Kumar et al., 2007, Nature Genetics).
  • A miRNA mimic has the same sequence as a naturally occurring miRNA and is therefore unlikely to have “off-target” effects. A miRNA mimic simply replaces the depleted endogenous miRNA, targeting the same genes that are also affected by the naturally occurring miRNA.
  • Since Mirna’s miRNA therapeutics are normal constituents of healthy cells, the inadvertent introduction of miRNA therapeutics into healthy cells may not result in toxicity. Thus, tumor-specific targeting of Mirna’s therapeutics is less likely to be necessary.

miRNA therapeutics are often compared with and sometimes confused with siRNA therapeutics (short interfering RNAs). Both, siRNAs and miRNAs function in the RNAi pathway and are similar in structure; however, the therapeutic applications of these follow distinct rationales and have distinct mechanisms of action and outcomes. The animation below illustrates the concept of miRNA replacement therapy and will clarify some of the differences between miRNA therapeutics and siRNA therapeutics.

Animation text:

In normal cells, a given tumor suppressor miRNA is expressed at a certain level that is required and sufficient in modulating gene expression to maintain a normal state of its associated pathways. Due to genetic aberrations, which are part of the cancer process, this miRNA might be expressed at a reduced level which results in increased levels of many mRNAs and consequently, increased activity of their associated pathways. Since many of these genes originally suppressed by the miRNA encode key oncogenes, the loss of the tumor suppressor miRNA may lead to a conversion to the cancerous state. siRNA therapeutic approaches take advantage of the RNAi pathway and are designed to target a single gene of interest and to induce complete degradation of the target. The rationale for choosing a particular siRNA target is based on scientifically sound projections of whether inhibition might provide a therapeutic benefit. The successful eradication of the intended target leads to an inhibition of the associated pathway.

Mirna’s miRNA Replacement Therapy seeks to replenish the missing tumor suppressor miRNA by introducing a mimic of the tumor suppressor miRNA. This miRNA mimic functions similarly to the endogenous miRNA and modulates the entire spectrum of genes and pathways that is also controlled in normal cells by the endogenous miRNA. Thus, tumor suppressor miRNA mimics provide an opportunity to target multiple cancer-relevant genes in a fine-tuned manner. Considerations of “off-target” effects and the selection of the “best target” become irrelevant as miRNA mimics behave like the natural counterparts for which the proper miRNA-target interactions have evolved over a billion years.