Charité – Universitätsmedizin Berlin

Department of Cardiology, Cardiovascular Medicine

 

Wolfgang Poller

Molecular therapy and RNA technologies

The unifying research theme of our working group is the use of high throughput screening strategies for the identification of new therapeutic targets in heart failure and cardiomyopathies, and the development of novel molecular therapies for their treatment.

The search for new therapeutic targets is increasingly focused upon immune-related processes and noncoding RNAs including microRNAs, long noncoding RNAs, and RNA interference.

M.D. and Ph.D. students who are interested in these topics are most welcome to contact us: wolfgang.poller@charite.de or martina.gast@charite.de.

Expertise

Clinical Translational Project Management

Due to the translational nature of our research topic, we conduct most of our current work in close cooperation with clinical research colleagues. Through a research network we have also access to transregional patient cohorts and biosamples collected in years 2004 - 2013. During the search for novel therapeutic targets, we recently identified microRNAs (Kuehl et al. 2015, Kasner et al. 2016) and immune-related proteins (Escher et al. 2016, Escher et al. 2017) which on the one hand are useful as clinical prognostic biomarkers, and on the other hand may constitute new targets for therapeutic modulation.

Molecular Biology and Genetics of Immune System - Heart Interactions

Our own research and that of cooperation partners has recently focused on "immune system - heart interactions" as an important driving force for disease progression in cardiomyopathies and heart failure. With this in mind we currently study circulating immune-related markers reflecting the status of the diseased heart. This work evaluates novel markers (ncRNAs) associated with circulating exosomes or circulating immune cells (PBMCs) and test if these easily accessible markers have prognostic potential.

We hypothesize that exosomal signaling from irreversibly injured hearts is different from that from hearts with still ongoing pathomechanisms involving innate/adaptive immunity. Whereas traditional protein-type markers are not released before severe or irreversible injury to the cells has occurred, altered packaging and exosome-mediated release of "stress-indicators" may occur much earlier during any pathogenetic process imposing stress (e.g. volume or pressure overload, ischemia, infection) on the heart. Alongside these exosomal studies, PBMC-associated ncRNAs markers will be evaluated regarding their potential to distinguish irreversibly injured hearts from those with still ongoing pathomechanisms, with particular attention to immune-related local or systemic mechanisms. The latter may constitute new therapeutic targets. 

Nucleic Acid Therapeutics and RNA Interference for Cardiovascular Disease

New therapeutic targets of high interest may be related to common HF recovery markers. Recent new molecular targets with broad relevance unconfined to specific etiologies include regulators of myocardial Ca2+ cycle. Related therapies are SERCA2A gene transfer (Greenberg et al. 2014) and PLB ablation using RNA interference (Suckau et al. 2009). Another target is miR-25 which was identified by ex vivo screening for modulators of cardiomyocyte function. It was then found that miR-25 inhibition improves cardiac contractility in the failing heart in vivo (Wahlquist et al. 2014). Former publications from our group regarding gene or RNA based therapies are given below.

Along these strategies of research, we currently try to identify "myocardial recovery" targets by screening particularly well characterized HF patients under maximum therapy who show differential response to treatment. We have identified potential non-coding RNA targets (miRs, lncRNAs) which are now being further evaluated. The therapeutic tools employed by our group include AAV9 vectors for gene and RNAi therapy targeted to the heart in vivo, and synthetic small RNAs (siRNAs, miR mimics, ASOs) delivered directly or using nanoparticles.

Interested in collaborating on

Clinical Translational Studies

We expect and anticipate support from Cardiolinc members regarding the acquisition and analysis of cardiovascular disease populations. Cooperation within Cardiolinc enables extension of our current work on non-coding RNAs to significantly larger and equally well characterized patient and control cohorts. In general, work within this network and participation in Cardiolinc meetings will provide us with new ideas and opportunities regarding translation.

Molecular Biology and Genetics of Immune System - Heart Interactions

Since many members of Cardiolinc are highly experienced in the immunobiology and immunogenetics of cardiovascular diseases, specifically regarding the roles of the non-coding genome, work within the network should significantly facilitate and promote the exchange of new ideas, analytical strategies, and laboratory research methods in this complex field.

Nucleic Acid Therapeutics and RNA Interference for Cardiovascular Disease

Similar as outlined regarding the immunobiology and immunogenetics of cardiovascular diseases, many Cardiolinc members have broad experience and sophisticated methods within the field of nucleic acid therapeutics in vitro and in vivo. We anticipate further facilitated interactions and exchange of ideas, and progress regarding laboratory research methods, and regarding the chemical as well as biological synthesis of nucleic acid therapeutics.

Selected publications on lncRNA

Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives
Poller W, Dimmeler S, Heymans S, Zeller T, Haas J, Karakas M, Leistner DM, Jakob P, Nakagawa S, Blankenberg S, Engelhardt S, Thum T, Weber C, Meder B, Hajjar R, Landmesser U. Eur Heart J. 2017.

Long noncoding RNA MALAT1-derived mascRNA is involved in cardiovascular innate immunity
Gast M, Schroen B, Voigt A, Haas J, Kuehl U, Lassner D, Skurk C, Escher F, Wang X, Kratzer A, Michalik K, Papageorgiou A, Peters T, Loebel M, Wilk S, Althof N, Prasanth KV, Katus H, Meder B, Nakagawa S, Scheibenbogen C, Schultheiss HP, Landmesser U, Dimmeler SHeymans S, Poller WJ Mol Cell Biol. 2016, 8(2):178-81.

Cardiovascular RNA interference therapy: the broadening tool and target spectrum
Poller W, Tank J, Skurk C, Gast M. Circ Res. 2013, 113(5):588-602.

Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy
Suckau L, Fechner H, Chemaly E, Krohn S, Hadri L, Kockskämper J, Westermann D, Bisping E, Ly H, Wang X, Kawase Y, Chen J, Liang L, Sipo I, Vetter R, Weger S, Kurreck J, Erdmann V, Tschope C, Pieske B, Lebeche D, Schultheiss HP, Hajjar RJ, Poller WCCirculation. 2009, 119(9):1241-52.

Website
wolfgang.poller@charite.de

Hindenburgdamm 30
12200 Berlin
Germany