These are the opening years of a period of barnstorming and experimentation in the modification of regenerative processes. A growing mountain of knowledge is under construction for all of the most important aspects of regeneration: stem cells, cellular senescence, immune cell activity, and so forth. The cost of tools used in the biotechnology field is falling even as the capabilities of those tools increase dramatically. Exploration of the biochemistry of regeneration has never been as easy and as cheap as it is today. A tipping point has either passed or lies just ahead, with the result being an expanding diversity of ways to adjust the self-repair of tissues - and to perhaps restore a more youthful, healthy degree of healing where it is impaired by aging, by inflammation, or by metabolic diseases such as diabetes.
One of the important challenges found in most areas of modern medical research is targeting. As it becomes possible to edit genes and selectively increase or decrease the amounts of specific proteins inside cells, it is also becoming increasingly important for such changes to be localized. The amount of a given protein in circulation is a switch or a dial in the machinery of cellular metabolism, but the same protein can have radically different roles in different tissue types. So while a global adjustment throughout the body is in many cases quite feasible to achieve today, it is in many cases a bad idea to try it. A beneficial change in one tissue might even prove fatal in another. Thus a wide range of approaches are at various stages of development when it comes to to targeting therapies to specific tissues, as the better and more reliable the targeting mechanism, the more options become available as a basis for medical development. The paper I'll point out today is one example of the type:
MicroRNAs are small gene fragments which bond onto target structures in cells and in this way prevent certain proteins from forming. As they play a key role in the occurrence and manifestation of various diseases, researchers have developed what are known as antimiRs, which block microRNA function. The disadvantage of this approach is, however, that the blockade can lead to side effects throughout the entire body since microRNAs can perform different functions in various organs. Researchers have now solved this problem.
The researcher have developed antimiRs that can be activated very effectively over a limited local area by using light of a specific wavelength. To this purpose, the antimiRs were locked in a cage of light-sensitive molecules that disintegrate as soon as they are irradiated with light of a specific wavelength. As a means of testing the therapeutic effect of these new antimiRs, the researchers chose microRNA-92a as the target structure. This is frequently found in diabetes patients with slow-healing wounds. They injected the antimiRs in the light-sensitive cage into the skin of mice and then released the therapeutic agent into the tissue with the help of light. Together the research groups were able to prove that pinpointed activation of an antimiR against microRNA-92a helps wounds to heal.
"Apart from these findings, which prove for the first time that wound healing can be improved by using antimiRs to block microRNA-92a, our data also confirms that microRNA-92a function is indeed only locally inhibited. Other organs, such as the liver, were not affected." The researchers now want to see whether they can also expand the use of light-inducible antimiRs to the treatment of other diseases. In particular they want to examine whether toxic antimiRs can attack tumors locally as well.
MicroRNAs (miRs) are small non-coding RNAs that post-transcriptionally regulate gene expression by binding to targeted mRNAs and thereby inducing degradation or blocking its translation. MiRs have important functions in different pathophysiological processes and diseases. Therefore, targeting miRs by application of specific miR inhibitors might have great therapeutic potential. MiRs can be inhibited by different types of antisense RNAs (antimiRs). Such antisense oligonucleotides are relatively easily taken up by detoxifying organs such as the liver or kidney, but uptake in other organs such as the muscle or brain tends to be limited. Local delivery or activation may be necessary to augment the biological functions of antimiRs in the target tissue and reduce systemic toxicity. Local activation might also avoid unwanted side effects of antimiRs, since miRs have diverse functions in different tissues.
Several targeting strategies have been experimentally used including the linking of miRs or antimiRs to aptamers, nanoparticle- or microparticle-mediated delivery and cell type-specific delivery by viral vectors as well as attempts of local delivery by mechanical tools, for example, catheters. In addition, we and others have developed photoactivatable antimiRs by attaching photolabile protecting groups (cages) to the nucleobases that temporarily inhibit duplex formation with the target miR, thereby allowing an excellent on/off behaviour upon irradiation.
However, the therapeutic in vivo use of light-activatable antimiRs has been unclear. Therefore, we tested whether light-activatable antimiRs directed against miR-92a can be used to locally augment impaired wound healing in diabetic mice. Inhibition of miR-92a was previously shown to improve angiogenesis and recovery after ischaemia; however, its regulation and function during wound healing, a process that is dependent on the angiogenic response, is unknown. Here we show that light-activatable antimiR-92a efficiently downregulate miR-92a expression leading to target gene derepression in the murine skin, thereby improving diabetic wound healing by stimulating cell proliferation and angiogenesis.