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Center for RNA Medicine

Research

Recent data imply that the human genome is pervasively transcribed and encodes tens of thousands of noncoding RNA (ncRNA) transcripts that play important regulatory roles in a wide array of cellular processes. Our main focus is to understand the biological functions of different classes of ncRNAs such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in human health and disease. We are currently pursuing several research projects that explore the roles of ncRNAs in the pathogenesis of cancer, non-alcoholic steatohepatitis (NASH) and obesity. Our long-term goal is to translate ncRNA discoveries into novel RNA-targeted therapeutic strategies for the treatment of life-threatening diseases.

      

THERAPEUTIC TARGETING OF METABOLIC microRNAs AS A NEW TREATMENT PARADIGM FOR NASH

NASH is a progressive subtype of nonalcoholic fatty liver disease characterized by abnormal fat accumulation in the liver, inflammation and fibrosis. NASH is strongly associated with obesity and the metabolic syndrome and is rapidly becoming the leading cause of end-stage liver disease, liver transplantation and hepatocellular carcinoma, underscoring the need for new therapies for treatment of NASH. This project focuses on developing miRNA-targeted therapeutics as a new treatment paradigm for NASH. Our goal is to discover drugs for effective and safe inhibition of metabolic miRNAs and assess their therapeutic potential to treat NASH in highly relevant preclinical models of NASH. Furthermore, we are evaluating hepatic and circulating miRNAs in human samples as biomarkers for NASH. We envision that the development of combined diagnostics and miRNA-targeted therapeutics has the potential to guide new treatment options for patients with NASH.

                        Steatohepatitis picro sirius

LONG NONCODING RNAs IN HEPATOCELLULAR CARCINOMA 

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths globally. Despite recent progress in development of HCC therapies, the median overall survival of advanced stage HCC patients is still only 12 months, which underscores the unmet medical need for novel therapeutic approaches for treatment of HCC. We aim to identify HCC-associated lncRNAs and circRNAs by RNA sequencing of HCC biopsies, uncover their molecular functions and evaluate the efficacy of design-optimized antisense oligonucleotide compounds targeting candidate lncRNAs in mouse models of HCC.

                        Hepatocellular carcinoma picro sirius

NONCODING RNAs IN MULTIPLE MYELOMA

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of malignant plasma cells in the bone marrow leading to tumor growth, anemia, immune suppression, and myeloma bone disease. We are interested in understanding the role of ncRNAs in the pathogenesis of MM and myeloma bone disease. Previous studies have shown that miR-138 is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and inhibiting its function enhances bone formation. We have explored the role of miR-138 in myeloma bone disease and showed that inhibition of miR-138 results in enhanced osteogenic differentiation of MM-MSCs in vitro and increases the number of endosteal osteoblastic lineage cells and bone formation rate in mouse models of myeloma bone disease. In addition, we are investigating the biological functions of selected lncRNAs associated with the pathogenesis of MM. 

                                          

TOOL DEVELOPMENT

Antisense oligonucleotides (ASOs) have emerged as useful tools for knockdown of ncRNAs and hold great promise as therapeutics for the treatment of a wide range of human diseases. Most ASOs are chemically modified with phosphorothioate (PS) backbone linkages and different sugar modifications such as locked nucleic acids (LNAs) to enhance the binding affinity, stability and pharmacokinetic properties of ASOs. We have developed a computational tool for designing LNA-modified ASOs for ncRNA knockdown in cultured cells and in vivo. Our algorithm utilizes two ASO design paradigms with different mechanisms of action. ASOs promoting degradation of long noncoding RNA transcripts are designed as RNase H-recruiting LNA-modified PS gapmers with a central DNA gap flanked by LNA wings at the 5’ and 3’ end of the gapmer. ASOs for inhibiting miRNA function (antimiRs) are designed as LNA/DNA mixmers or short fully LNA-modified oligonucleotides with a complete PS backbone.

                       Lung cancer cells