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MicroRNAs in heart disease

Custom miRCURY LNA™ microRNA in vivo Inhibitors

Dr. Stefanie Dimmeler
Dr. Reinier Boon
Stefanie Dimmeler, Professor and group leader, and Reinier Boon, Post Doctoral researcher, work in the Institute for Cardiovascular Regeneration at the Goethe University Frankfurt, Germany. Here they study the basic mechanisms underlying cardiovascular disease and vessel growth with the aim to develop new therapies to improve treatment of cardiovascular diseases. They have just published a paper on the role of age-dependent microRNA expression in the vasculature.

What is the current research going on in your lab?

We do cardiovascular research, both in vitro and in vivo and we work with patient material as well. For the last four years, 70% of our work has been focused on microRNAs.

How did your research lead you to the study of microRNAs?

We focused on miRNAs from the beginning of this study.

Did you have previous experience with in vivo studies?

Yes, we did a lot of in vivo studies before, but never with LNA™ inhibitors.

Why did you choose to use miRCURY LNA™ in vivo inhibitors for your experiments?

We needed inhibitors that inhibited the expression of miR-29 in the aorta. We had experience with classical antagomiRs, but these did not work for knock-down in the aorta. The LNA™ -inhibitors did work quite well.

What specific question did you want to address?

We wanted to answer the question whether inhibition of miR-29 could prevent aneurysm formation in aged mice.

You initially found 18 highly age dependent microRNAs regulated in the aorta of mice. What drew your attention to the miR-29 family?

We performed unbiased screens with the mRNA microarray data we generated of aged and young aortas. The bioinformatics tools we used for this look for statistical enrichment of seed-target sequences in the 3’UTR of regulated genes. We found that in the aged aorta there is an enrichment for miR-29 target genes among the down-regulated genes.

Finding the right dosage or administration for the targeted organ can be major obstacles, What were your experience regarding this?

This was relatively straightforward: We took the concentrations known from the literature and went a bit higher. Finding the right chemistry (long vs short sequences, cholesterol-modified vs non-modified) that would target the aorta was harder to do.

How were the in vivo inhibitors tolerated? Did you observe any adverse reactions?

They were well-tolerated. We did not notice any adverse reactions. Even though inhibition of miR-29 has been shown to cause fibrosis in different organs, we did not see this. It is of course possible that the effects on fibrosis are only visible after the right stress for the organ.

What were some specific challenges in your in vivo experiments?

We did not study aneurysms before, so finding and setting up the right model systems was a lot of work.

How did you overcome them?

We had help from other groups on the campus and even from a visiting scientist.

What parameters do you recommend to monitor when doing in vivo experiments?

This depends a lot on the process you are studying and the effects of the microRNA that you inhibit.

How do you feel about the results you obtained?

We hope that we have opened up a new way to combat aneurysm formation and/or progression in the near future.

Which new scientific implications or follow up experiments come to your mind with respect to the results you obtained?

The next obstacle to tackle would be to demonstrate the anti-aneurysmic effects of miR-29 inhibition in a larger animal model. As these models have not been established, this will prove challenging.

What advice would you give to researchers who want to get started in miRNA in vivo inhibition experiments?

Decide whether you want to inhibit a single microRNA or an entire family, then ask Exiqon to design inhibitors and do a dose-finding experiment for the organ you want to target.

What would you tell a colleague about why they should work with Exiqon?

The LNA™-inhibitors from Exiqon just work.

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