February 1, 2014 (Vol. 34, No. 3)

Enal Razvi Ph.D. Managing Director Select Biosciences

Despite Great Challenges, a Number of Companies Are Committed to Development Programs

Currently, there are two segments of the microRNA research marketplace that are translating toward the clinic: miR signatures as biomarkers with utility in diagnostics development and modulating miRs therapeutically as a means to modulate disease.

The former segment is perhaps the most visible as there are a large number of publications documenting the association of specific microRNA expression patterns (signatures) with specific physiological or pathological (disease) situations. This is best exemplified in the case of the oncology space where microRNA expression dysregulation has been observed in a number of different cancer sub-types and in some cases the molecular basis of the microRNA defect has been elucidated.

The more challenging market segment is the translation of microRNA therapeutics into the clinic. Indeed, the potential exists for microRNA-modulating agents to be therapeutically administered and thereby affect gene expression in vivo in an effort to tip the balance toward a biological phenotype. The challenge in translating microRNAs from research toward therapeutic utilization is that a given microRNA is known to modulate the expression of several genetic elements; therefore, the up-/down-regulation of a given microRNA is expected to broadly affect several genes in vivo.

In spite of this challenge, there is a movement of specific microRNA species toward the clinic. The table presents the microRNAs where therapeutic significance has been documented and that are currently being targeted in preclinical/clinical programs.

There is extensive interest in miR-21 centered around its role in “maintaining” solid tumors by way of blocking the programmed cell death pathway in vivo. Various classes of solid tumors have miR-21 associated with them. Regulus Therapeutics has programs modulating miR-21 in hepatocellular carcinoma (HCC) and renal fibrosis.

miR-34 is downregulated in many cancers—solid tumors as well as hematological (liquid) tumors. Therefore it is believed to be a tumor suppressor miR in vivo—some reports have referred to it as a “master tumor suppressor” given that it is associated with many different cancer classes.

Mirna Therapeutics is focused on restoring loss-of-function of miR-34 via a mimic delivered in vivo using a nanoparticle-based delivery approach. The company has begun a Phase I trial focusing on miR-34-based therapy in unresectable primary liver cancer or metastatic cancer with liver involvement.

This microRNA has received by far the most attention vis-à-vis its therapeutic potential. The source of the interest is driven by the fact that hepatitis C virus (HCV) requires in its life cycle cell-derived miR-122. Cell lines with low levels of endogenous miR-122 are refractory to HCV infection—upregulation of miR-122 via transfection makes these cell lines permissive to HCV infection.

Furthermore, HCV infection is a prelude to HCC and therefore a strategy of miR-122 downregulation via a therapeutic strategy is devised to therapeutically target HCV infection and downstream HCC event. Regulus Therapeutics and Santaris Pharma are involved in miR-122 targeting.

Beyond cancer, there are programs in cardiovascular disease being developed by Miragen Therapeutics focusing on heart failure, myocardial infarction, and vascular disease.

InteRNA Technologies has active programs targeting specific microRNAs in cancer as well as in neurodegenerative diseases.

In summary, there a number of therapeutic programs ongoing seeking to modulate microRNA levels in vivo in a number of disease areas including cancer and beyond. This remains an active space and although the challenges are great, it remains an attractive therapeutic modality for the future.


microRNAs Targeted for Therapeutic Purposes






























Enal Razvi, Ph.D. (enal@selectbio.us), is biotechnology analyst, managing director at Select Biosciences.