Challenges in miRNA therapeutics development

Micro RNA, a class of non-coding single-stranded length RNA containing about 22 nucleotides, is closely related with significant disease such as tumors, heart disease and neurological diseases, and thus becoming an important new target for drug development. However, several problems are still need to be resolved in the development of miRNA therapeutics.

The most difficult issue is the hybrid-related off-target effects. The miRBase currently has a collection of 2,578 of human miRNAs. Many miRNAs have similar sequences such as miR-17 and let-7 family. Furthermore, MiRNA family members of the same class are often difficult to distinguish from each other. It’s also been reported that the 2'-O-methyl modified miR-93 inhibitor can inhibit other members of the family, such as miR-106b.

Meanwhile, for miRNA, there also exist another hybridize unrelated off-target effect. Nucleic acid drugs may stimulate the immune system, and result in severe immune toxicity. Although chemical modification could increase the affinity and stability of oligonucleotide, it also brought sequence independent toxicity.

The last question is how the the miRNA drugs should be given. This is a general problem in all the nucleic acid drug development for nucleic is unstable in blood and not easily to penetrate cell membranes. So, how to deliver the drug from in vitro to in vivo is a problem, furthermore, how to deliver the drug to the diseased tissue and avoid systemic toxicity also a problem. If one day the drug delivery problem for miRNA is really solved, would RNA become the third largest category drugs since small molecule, and protein?

Embelin, extracted from Japanese Ardisia Herb, is a strong non-peptide and cell permeability XIAP inhibitor. German researchers have found that it can be used to inhibit tumor angiogenesis, thereby slowing tumor growth. This work had been published on "EMBO Mol Med" in May 2014.

Researchers from the University of Cologne said that it has become a common practice to repress tumor growth by blocking growth factors and inhibiting angiogenesis.

The researchers found that Embelin can be used as "poison" to the mitochondria of cancer cell. The mitochondria of cells is called "power plant" because they generate most of the cell's supply of adenosine triphosphate(ATP), used as a source of chemical energy. Embelin inhibits endothelial mitochondrial respiration and impairs tumor angiogenesis during tumor growth, whereas normal blood vessels and tissues are not affected significantly.

Meanwhile, in wound healing experiments researchers also found that the use of embelin could block angiogenesis and slow wound healing. The researchers believe that this is further verified the mechanism of action Embelin.

The researchers said that embelin could inhibit tumor angiogenesis with fewer side effects, this new drug may be used for effectively reduce tumor growth.

Ref: Coutelle O, Hornig?Do H T, Witt A, et al. Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing[J]. EMBO molecular medicine, 2014.

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