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This approach, also known as miRNA replacement therapy, has attracted much interest as it provides a new opportunity to therapeutically exploit tumor suppressors. While siRNAs are designed to repress a single mRNA of interest, miRNA mimics inherently target multiple transcripts, now providing a unique mechanism of action that guides the process for drug development and sets forth the context of its therapeutic application.

For instance, as the miRNA itself becomes the therapeutic entity, the primary rationale for its application should be based on its expression levels in diseased tissues rather than on the identity and status of selected target genes. Using this approach, the quest for target genes responsible for the miRNA-induced phenotype becomes theoretically irrelevant, because the mimic carries the same sequence as the endogenous miRNA and is expected to regulate the same, all-inclusive set of genes. This is of particular interest, as a given miRNA can regulate several hundreds of genes, and identifying all genes critical to miRNA function could become a tedious, if not impossible, task.

Nonetheless, information about genes and pathways regulated by the miRNA may prove useful in understanding its mechanism of action, monitoring miRNA activity and designing clinical trials. An example for applying a miRNA mimic in the appropriate context is provided by let -7, a miRNA expressed at reduced levels in self-renewing tumor-initiating breast cancer cells.

However, restoring the levels of let -7 had superior anti-oncogenic effects. Interestingly, the therapeutic application of miRNA mimics is not limited to replacement and can also provide the desired response in disease cells with normal miRNA expression levels. For instance, adding miRa, a tumor suppressor frequently expressed at reduced levels in various cancer types, not only inhibited the growth of cancer cells devoid of miRa but also of those that show normal levels of endogenous miRa.

Thus, there appears to be an added value for miRNA mimics; however, it remains to be determined what patient will benefit from it. As miRNA mimics behave like endogenous miRNAs, another aspect to consider is the selection of appropriate assays and measures during drug development. Although the therapeutic activity of miRNA antagonists can be assessed by monitoring the levels of the endogenous miRNA, a phenotypic readout, such as efficacy in a cell or animal model, is usually the preferred method to monitor the activities of miRNA mimics. This approach applies to situations where the chemistry of the mimic has not been finalized and chemical modifications may alter miRNA specificity and functionality.

The preference for a phenotypic assay over monitoring one or few target genes is based on the fact that the repression of few mRNAs may not be representative for its overall activity but, rather, may direct development programs into generating compounds with altered, and thus, incorrect target specificity.

An alternative to phenotypic assays are genome-wide mRNA expression analyses that can capture all miRNA-induced changes to the transcriptome. Once the chemistry of the mimic has been finalized, single target genes that provide satisfactory sensitivity can be used as biomarkers to monitor therapeutic activity.

Developing active pharmaceutical ingredients that either target or mimic specific miRNAs involves creating oligonucleotides with favorable pharmacological and pharmacokinetic properties. The generation of miRNA antagonists has been achieved by antisense oligonucleotides that are partially or completely complementary to specific miRNA sequences. The length and chemical composition of antisense oligonucleotides can be optimized to improve circulation time, cellular internalization and activity, and to enable systemic delivery without a delivery agent. This activity can be mimicked using a synthetic, single-stranded RNA molecule that contains the same sequence and chemistry as the mature endogenous miRNA.

Consistent with results published for siRNAs, 21 however, the potency of singled-stranded miRNA mimics tend to be —fold less compared with mimics that feature a second, complementary strand. Therefore, double-stranded miRNA mimics are greatly preferred to single-stranded mimics. The passenger strand can either be perfectly complementary to the mature miRNA or it can incorporate mismatches that are consistent with the precursor form that is produced naturally in cells.

As with other oligonucleotide-based therapeutic candidates, nucleotide analogs can be used to improve the activities and half-lives of miRNA mimics. Terminal modifications such as inverted bases, biotin, alkyl groups and others can be added in the passenger strand without negatively affecting the activity of the miRNA mimic unpublished data.

Although nucleotide analogs can significantly enhance the half-lives of the synthetic miRNAs, they can also affect the hybridization kinetics and melting temperatures and, consequently, target specificities of the molecules. As miRNA replacement therapy depends on providing patients with miRNA activities that are identical to those that are reduced or missing in the disease cells, measuring target specificity is an essential component when developing a miRNA mimic Box 1.

Changes in miRNA activity and target specificity are often a result from terminal modifications in the active strand and a high degree of modification in the central regions of both strands.

Micrornas As Tools In Biopharmaceutical Production

As the specific, pharmacologically optimal combinations of modifications vary for each miRNA, creating custom-made chemistries for each active pharmaceutical ingredient candidate is highly recommended. Increasing evidence demonstrates that miRNAs are promising agents in cancer therapy. However, similar to other therapeutic oligonucleotides, the main challenge remains the successful delivery of the therapeutic miRNAs to the target tissue without compromising the integrity of the miRNA reviewed in Akhtar and Benter, 23 Castanotto and Rossi, 24 Kaasgaard and Andresen, 25 Whitehead et al.

Naked ribonucleic acids are subject to rapid nuclease dependent degradation and are therefore inherently unstable in biofluids. Thus, many therapeutic applications of RNAi are limited to local administration for which exposure of the RNAi agent to potential degradation mechanisms is restricted to a minimum. However, local administration is merely applicable to a short list of target tissues and frequently does not facilitate exposure of all disease cells to the drug. Systemic delivery is therefore a better route of administration because—in theory—it provides a much more efficient dissemination of the therapeutic to target tissues.

Next to rapid degradation by serum nucleases, however, the miRNA will have to overcome many obstacles before it reaches the target Box 2. In addition, systemic delivery of miRNAs may induce similar adverse events that have been reported for other oligonucleotide-based therapies, such as aggregation and complement activation, liver toxicity and stimulation of an immune response by the nonspecific activation of toll-like receptors. As miRNA antagonists and mimics are chemically similar to antisense oligonucleotides and therapeutic siRNAs, many technologies developed for these may also be applicable to miRNAs.

Therefore, the development of clinically relevant miRNA formulations frequently involves a thorough evaluation of existing technologies to identify those that are amenable to the miRNA and its chemistry. Criteria critical in the evaluation process are i sufficient delivery to induce a therapeutic effect in disease models and ii a significant safety margin at therapeutic levels.

Several technologies have proven effective in delivering therapeutic miRNAs to tumor tissues in vivo. These include vector-based systems that were originally developed for gene therapy. This model is based on an activating KRAS mutation that is also prevalent in human cancers and leads to tumors that resemble those in man. Of note, MYC is not a direct target of miRa and, therefore, the inhibitory activity of miRa is attributed to the repression of other genes presumably downstream of oncogenic MYC.

Another example for in vivo delivery of a miRNA-based therapeutic is provided by miRb. This miRNA is transcriptionally induced by TWIST, a transcription factor that contributes to epithelial—mesenchymal transitions and functions in high-grade malignancies. As predicted, systemic delivery of the miRb antagomiR prevented the formation of metastases that are usually produced by the primary orthotopic 4T1 breast cancer xenograft.

In contrast to miRb, however, miR functions as a tumor suppressor that is downregulated in tumor cells of the prostate and—when re-introduced—induces apoptosis. As atelocollagen is a natural product, these nanoparticles are considered to be highly biocompatible and seem to achieve tumor-specific delivery via enhanced permeability and retention.

Although miRb seems to play a role in pathways that control invasion and early stages of metastasis, the effects of miR appear to be due to a repression of cell cycle genes. It is possible that a combination of the miRb antagonist and miR mimic might prove particularly effective in treating cancer patients.

A candidate that has attracted much interest for therapeutic development is miRa. It is downregulated in a broad variety of different cancer types. Proof of concept for its therapeutic activity was demonstrated in mouse models of non-small cell lung cancer. In addition, miRa mimics formulated in the neutral lipid emulsion failed to induce elevated levels of neither cytokines nor liver and kidney enzymes in serum, suggesting that tumor inhibition was a specific effect of the mimic and that treatment was well tolerated.

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The discovery and characterization of miRNAs has provided exceptional opportunities for the development of new therapeutics for human diseases. Regulatory guidelines, however, have not kept pace with the rapid growth of this new class of therapeutics. This lack of definition creates an opportunity for a case-by-case approach in designing the non-clinical development programs. The goal of any non-clinical testing program is to provide the rationale for conducting human studies, characterize the pharmacokinetic profile, identify potential adverse drug effects and define a safety margin for human clinical studies.

As miRNAs are chemically synthesized, the expectation is that miRNAs will be reviewed under the guidelines for small molecules. ICH-S9, Non-clinical Evaluation of Anticancer Pharmaceuticals, provides information on the program design of non-clinical studies to support the development of anticancer pharmaceuticals. As noted in this guidance, genotoxicity studies and separate safety pharmacology assessments are not a requirement to support an initial clinical trial for an oncology indication. It is generally expected that the toxicology studies will be conducted in a rodent and non-rodent species.

As miRNA sequences are highly conserved across species, there are no apparent restrictions on species selection or a requirement to develop analogues or surrogates, as has been the case with non-conserved oligonucleotides. The dose levels can be established according to data obtained from pharmacology studies and non-GLP dose-ranging studies in the selected tox species. Delivery not available.

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