Therapeutic targets involved in the progression of nonalcoholic steatohepatitis (NASH)
Inventors
Tabas, Ira • Wang, Xiaobo • Farokhzad, Omid • Xu, Xiaoding
Assignees
Brigham and Womens Hospital Inc • Columbia University in the City of New York
Publication Number
US-12285464-B2
Publication Date
2025-04-29
Expiration Date
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The present invention relates to methods and compositions for specifically modulating the Hippo pathway transcription factor TAZ (WWTR1), as a therapeutic target for inhibiting or preventing liver conditions including the progression of steatosis-to-NASH in a patient.
Core Innovation
Nonalcoholic steatohepatitis (NASH) has emerged as the leading cause of chronic liver disease worldwide, and there is a dearth of treatment options largely due to a poor understanding of how benign steatosis progresses to NASH. There is a great need for improved models that mimic the relevant human disease conditions, as well as for new therapeutic targets for treating or preventing NASH and related conditions.
The present invention relates to methods and compositions for specifically modulating the Hippo pathway transcription factor TAZ (WWTR1), as a therapeutic target for inhibiting or preventing liver conditions including the progression of steatosis-to-NASH in a patient. In certain embodiments, the invention provides methods for treating or preventing a liver condition comprising administering a therapeutically effective amount of an inhibitor of TAZ, wherein the inhibitor of TAZ is selected from the group consisting of proteins, nucleic acids (including antisense oligonucleotide, siRNA, shRNA), and combinations thereof, and wherein specific nucleic acids include SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:55-SEQ ID NO:72, and SEQ ID NO:81. The invention also provides pharmaceutical compositions, nanoparticle formulations comprising a hydrophobic inner core, a hydrophilic outer shell, and a hepatocyte targeting ligand, combination therapies (including inhibitors of Indian hedgehog (Ihh), YAP, TEAD1-4, and antidiabetic/insulin sensitizers), methods for diagnosing NASH or susceptibility to NASH by detecting elevated levels of TAZ, Ihh, YAP, TEAD1-4, and methods for monitoring liver treatment by detecting TAZ levels.
Claims Coverage
One independent claim identified. The independent claim recites a treatment method and specifies a nucleic acid-based inhibitor of TAZ complementary to human TAZ.
Method for treating progression of steatosis to NASH by TAZ inhibition
A method for treating or preventing progression of steatosis to non-alcoholic steatohepatitis (NASH) in a patient comprising administering to the patient a therapeutically effective amount of an inhibitor of TAZ.
TAZ inhibitor comprising nucleic acid complementary to human TAZ
The inhibitor of TAZ is recited as a nucleic acid comprising a sequence complementary to a sequence encoding human TAZ, where the nucleic acid is selected from antisense oligonucleotide, siRNA, shRNA, and combinations thereof, and includes sequences set forth as SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:55-SEQ ID NO:72, or SEQ ID NO:81.
The independent claim centers on a therapeutic method to prevent steatosis-to-NASH progression by administering a TAZ inhibitor and specifically claims nucleic acid inhibitors complementary to human TAZ, including enumerated SEQ ID NOs.
Stated Advantages
Inhibiting or preventing liver conditions including the progression of steatosis-to-NASH by specifically modulating TAZ (WWTR1).
Hepatocyte-specific TAZ silencing suppresses hepatic inflammation, hepatocyte death, and fibrosis without affecting steatosis.
Nanoparticle hydrophilic outer shell increases blood circulation half-life and provides immune system evasion.
TAZ nucleic acid or protein levels serve as markers for diagnosing susceptibility to NASH or ongoing NASH and for monitoring responsiveness to treatment.
Redox-responsive nanoparticle platform enables systemic delivery of siRNA with desirable blood circulation and targeted accumulation in liver tissue.
Documented Applications
Methods for treating or preventing liver conditions selected from fatty liver disease, non-alcoholic fatty liver disease, adiposity, steatosis hepatis, steatohepatitis, and non-alcoholic steatohepatitis (NASH) by administering an inhibitor of TAZ.
Administration of TAZ inhibitors to hepatocytes, including use of proteins, nucleic acids (antisense oligonucleotide, siRNA, shRNA), and specified SEQ ID NOs.
Pharmaceutical compositions comprising at least an inhibitor of TAZ alone or in combination with inhibitors of Ihh, YAP, TEAD1-4, and optionally with additional therapeutic agents such as antidiabetic drugs and insulin sensitizers (Rosiglitazone; Pioglitazone; Losartan; Simtuzumab; GR-MD-02; Obeticholic acid (OCA)).
Formulation of nucleic acid TAZ inhibitors in nanoparticles comprising a hydrophobic inner core, a hydrophilic outer shell, and a hepatocyte targeting ligand for liver-targeted delivery.
Methods for diagnosing NASH or susceptibility to NASH by detecting an elevated level of TAZ, Ihh, YAP, TEAD1-4 or combinations thereof, including in vitro nucleic acid detection assays using primers (e.g., forward primer SEQ ID NO:5 and reverse primer SEQ ID NO:6) and threshold control levels.
Methods for monitoring liver treatment in a patient being treated with an inhibitor of TAZ (and/or inhibitors of Ihh, YAP, TEAD1-4) by performing nucleic acid detection assays to detect TAZ levels and determining responsiveness based on reference TAZ levels.
Use of kits comprising viral vectors, RNAi, shRNA, TAZ inhibitors, or TAZ/IHH/YAP-based inhibitor compounds, optionally including primers, buffers, and probes with instructions for determining elevated levels of TAZ, Ihh, YAP, TEAD1-4.
Interested in licensing this patent?