3018

Anti-miR132 for The Treatment of Liver Diseases

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

 

Category

Life Sciences and Biotechnology   

Keywords

Liver, RNA, miRNA

Current development stage

TRL4 - POC & Safety of candidate drug formulation is demonstrated in defined animal modelvvvid demonstrated in  defined animal model

Application

Hyperlipidemia is a widespread condition that affects as many as one-third of adults and an increasing number of children in developed countries. Its pathogenesis mechanisms are only partly understood.

  • The small non-coding microRNAs (miRs) repress the expression of target mRNA transcripts, including metabolic ones. Each miR can target many genes and each target can be silenced by numerous miRs, but the impact of this complexity is still an enigma.
  • miR-132 is causally involved in cell proliferation, epigenetic regulation, anxiety reactions and intestinal inflammation, but has not been studied in the metabolic context.

Our Innovation

Inventor findings demonstrate that miRNA-132 mediated changes may lead to impaired lipid homeostasis and identify miRNA-132 as a promising target for therapeutic intervention with hyperlipidemia and obesity-associated metabolic diseases.

The researchers discovered a unique function of miR-132 as a novel context-dependent rheostat that regulates hepatic lipid metabolism by finely tuning multiple targets in diverse conditions, hopefully establishing the basis for a deeper understanding and an innovative treatment of hepatic lipid metabolism disorders of various aetiologies.

 

Advantages

  • MiRNAs act rapidly and effectively to block expression of their multiple target transcripts and operate at the network level.
  • Exceptional efficacy and unusually rapid and effective response of the AntiMiR-132 antisense agent makes it a highly innovative and valuable research tool for exploring new avenues for hyperlipidemia treatment.
  • Synthetic ‘antisense’ oligonucleotides offer important research advantages due to their high target specificity, wide target range and low molar dose required.

 

Pre-clinical results

Conditional miR-132 overexpressing transgenic mice, mouse models with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and human liver tissues from patients with NAFLD, all show increased hepatic miR-132, and decreased metabolism related miR-132 target proteins, thus validating miR-132 as an important regulator of hepatic lipid homeostasis.

  • In vivo suppression of miR-132 in diet-induced obese mice reversed hepatic steatosis and hyperlipidaemia, unlike the partial and limited impact of suppressing individual miR-132 targets.
  • miR-132 operates high in the hierarchy of hepatic lipid homeostasis by simultaneously suppressing multiple regulatory transcripts.
  • Metabolic cage tests demonstrate inverse patterns of energy exploitation in transgenic mice over-producing miR-132 and fattened mice treated with antisense oligonucleotide targeted to miR-132.

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The transgenic model: Peripheral miR-132 excess leads to multiple target reductions in diverse tissues, and associates with hepatic steatosis and impaired lipid homeostasis. (A) Schematic representation and expression levels of the engineered doxycycline-inducible double transgenic miR-132 system: the reverse tetracycline controlled transactivator (rtTA) followed by a β-globin Poly A sequence is located downstream of the Gt(ROSA)26Sor promoter and the ColA1 locus. Pre-miR-132 under the Tet-responsive Ptight promoter followed by an SV40 Poly A was expressed in progeny of rtTA-miR-132 double transgenic mice (miR-132 dTg). The rtTA protein (orange squares) binds in trans to the TREmod element in the presence of doxycycline, allowing pre-miR-132 transcription. Excess miR-132 levels in rtTA and miR-132 dTg mice were observed in the intestine, liver and spleen and heart but not adipose tissue and hippocampus (n=12 for rtTA tg, n=5 for miR-132 dTg, n=3 for rtTA and miR-132 dTg for adipose tissue).

 

Opportunity

Hyperlipidemia is strongly associated with obesity, insulin resistance and major adverse cardiac events (MACE), but its pathogenesis remains poorly understood, and at present no standard treatment exists. Using AS132 as a treatment of hyperlipidemia is hence a new and exciting opportunity.

MiR-132 levels can serve as a biomarker for assessment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

MiR-132 may become a target for developing and accessing novel NAFLD/NASH treatment strategies.

Related publication: https://www.ncbi.nlm.nih.gov/pubmed/28381526

 

 

Contact for more information:

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