A8*
Inhibition of TGFβ1-induced Long Non-Coding RNAs Prevents Cardiac Fibrosis
Prof. Thomas Thum, Hannover Medical School; Prof. Christian Bär, Hannover Medical School
Ascenion GmbH
Challenge
Fibrosis and related cancers constitute a growing and under-addressed burden in global healthcare, affecting a wide spectrum of organs, most notably the heart, lungs, liver, and kidneys with often irreversible consequences. Existing treatments for these diseases largely target symptoms or slow progression, but rarely offer reversal of pathology or address the root cause of abnormal fibroblast activation and extracellular matrix remodeling. Additionally, the lack of specificity and undesirable side effects associated with broad-acting protein- or growth factor-based interventions, such as those targeting TGFβ1, limits the treatment options.
This proprietary technology establishes the therapeutic and diagnostic potential of specific long non-coding RNAs (IncRNAs) as critical targets in the management of fibrotic diseases and cancer. The novelty lies in identifying a set of 17 IncRNAs with pronounced deregulation in pathologically activated fibroblasts, particularly after TGFβ1 stimulation. The invention provides pharmaceutical compositions capable of either inhibiting or promoting the expression/activity of pathology specific IncRNAs, substantiated by RNA sequencing, validation in human fibroblasts, and in vitro functional analyses. The approach integrates recent advances in antisense oligonucleotide therapeutics, enabling RNA-guided precision modulation. Furthermore, the technology also includes kits for direct and reliable IncRNA quantification in clinical diagnostics.
Technology
The present technology encompasses a panel of 17 IncRNAs with tightly regulated expression patterns observed in activated human fibroblasts, especially following TGFβ1-induced fibrotic stimulus. These IncRNAs (SEQ ID NOs 1–17) serve as dual-purpose molecular switches: the upregulated IncRNAs (SEQ ID NOs 1–14) drive fibrotic and oncogenic processes, whereas the downregulated subset (SEQ ID NOs 15–17) exhibits protective or anti-fibrotic properties. The invention offers multiple pharmaceutical compositions, comprising small molecules, nucleotide-based (siRNA, LNA-GapmeRs, shRNA, antisense), or protein-based inhibitors (e.g., aptamers, antibodies), to specifically decrease the expression and/or functional activity of pro-fibrotic IncRNAs.
Commercial Opportunity
The invention provides a first-in-class strategy for the diagnosis and treatment of fibrosis and cancer by precisely modulating highly selective lncRNAs within the fibrogenic pathways of human tissues. This represents a transformative leap in controlling diseases characterized by excessive fibroblast activity, such as cardiac, lung, liver, and kidney fibrosis. Thus, the technology adresses pathologies with limited reversibility and often poor prognosis. By using IncRNA-specific inhibitors (including antisense oligonucleotides such as LNA-GapmeRs and AntagomiRs, siRNAs, shRNAs, etc.), the technology enables profound downregulation of pro-fibrotic and pro-tumorigenic gene programs. Conversely, the capacity to promote the activity of protective IncRNAs adds therapeutic versatility, expanding the scope to both fibrotic suppression and recovery of tissue homeostasis. The invention offers pre-validated RNA targets, efficient nucleic acid-based drug modalities with proven cellular uptake and specificity, enabling disease-modifying treatments for fibrotic diseases.
Development Status
Validated in vitro. Two lead candidates under current evaluation.
Patent Situation
Priority date June 2022, international PCT-application pending (WO 2024/003205 A1)
Further Reading
Not yet published.
