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tRNA Fragments for the Diagnosis and Treatment of Metabolic Diseases

Soreq Hermona, HUJI, Faculty of Science, The Alexander Silberman Institute for Life Sciences

 

Category

Life Sciences and Biotechnology   

Keywords

Metabolic Syndrome, Transfer RNA fragments, Fatty liver disease, Diagnostics, Antisense oligonucleotide therapeutics, Biomarkers, Hepatic hyperlipidemia

Current development stage

For Pharmaceutical development: TRL3 - hypothesis testing and intial POC demonstrated in limited # of in-vitro models

Application

The prevalence of obesity and metabolic syndrome (MetS) are is rising worldwide, and are intimately linked with stress and trauma. However, the underlying molecular mechanisms are elusive.

The great majority of the human genome is comprised of non-coding RNAs, including long non-coding RNAs (lncRNAs), transfer RNAs and their processed fragments (tRFs) and microRNAs (miRs). Specifically, cleavage of the 5’- and 3’-loops in tRNAs produces short non-coding tRFs, tRF-5s and tRF-3s, some of which can act like miR molecules, interact with mRNAs carrying complementary sequence motifs and regulate their expression.

We are examining the roles of these non-coding RNAs in MetS using RNA-sequencing of: 1. Liver tissue from diet–induced obese mice exhibiting MetS-like characteristics (e.g. insulin resistance, glucose intolerance and fatty liver); 2. Human fatty/healthy liver samples following gastric bypass; 3. Human cell cultures exposed to long fatty acids. We have recently discovered rapid and effective decreases in fatty liver symptoms following the treatment of hyper-lipidemic mice with a chemically protected antisense oligonucleotide.

Our research has shown that this treatment induces profound changes in specific hepatic tRFs which target disease-relevant transcripts. Our findings combine two inter-related short RNA families, miRs and tRFs to initiate better diagnosis and treatment modules for hepatic hyperlipidemia.

Our Innovation

tRF sequences can become novel diagnostics for hepatic hyper-lipidemia and its receding levels under treatment: Hepatic hyperlipidemia is accompanied by elevated inflammation. We identified increases in certain blood cell tRFs in individuals with inflammation compared to healthy controls, indicating diagnostic advantages for detecting specific tRFs in blood cells from patients with hepatic hyperlipidemia. Cell culture use of tRF-targeted antisense oligonucleotides will provide proof of concept of these tRF candidates to the disease.

Modulated hepatic tRFs reflect the biological pathways involved: RNA-sequencing demonstrated elevation in blood cells from patients with inflammation of tRFs targeting transcripts.

Technology

To challenge the relevance of hepatic and blood tRF changes for hepatic hyperlipidemia, we will grow cell lines of human hepatic and blood cells origins, expose them to stressful insults known to compromise their metabolic functions and seek differences in tRFs and their potential target transcripts as well as up-regulated tRNA-targeting nucleases by RNA-sequencing, size-selected qPCR validations and enzyme activity tests.

Opportunity

The increase in specific tRF levels in malfunctioning hepatic cells at large and the link of their target mRNAs to hyperlipidemia via cholinergic blockade of inflammation offers prospects for diagnosis and follow-up of therapeutic treatments in hyperlipidemia patients.

 

Contact for more information:

Mel Larrosa
VP Business Development Healthcare
+972-2-6586692
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