{"id":"05857","slug":"targeting-stat5-and-tert--05857","source":{"id":"05857","dataset":"techtransfer","title":"Targeting STAT5 and TERT Interactions to Halt Ectopic Cardiovascular Calcification","description_":"

This invention utilizes Signal transducer and activator of transcription 5 (STAT5) and/or Telomerase reverse transcriptase (TERT) inhibitors to treat and prevent ectopic calcification in cardiovascular systems, tissues, and medical devices. By disrupting the specific molecular interplay that initiates osteogenic reprogramming, this therapeutic approach offers the first viable non-surgical method to prevent, halt, or reverse tissue hardening and device degradation within the circulatory system.

Description

The technology is based on the discovery that inflammation promotes the upregulation and interaction of TERT and STAT5 proteins during the early stages of cardiovasvular calcification. These two proteins physically interact to form a complex that translocates into the cell nucleus, where TERT facilitates the binding of STAT5 to the promoter region of the RUNX2 gene. This molecular binding initiates the osteogenic reprogramming—or bone-like transition—of local cardiovascular cells, leading to abnormal calcium deposition and tissue hardening. \r\n\r\nBy delivering a pharmaceutically effective amount of a STAT5 inhibitor (such as StafiA-1, StafiB-1, or pimozide) and/or a TERT inhibitor, the therapeutic method directly disrupts this protein-to-protein interaction. Preventing this complex formation reduces the osteogenic differentiation of valve interstitial cells, vascular smooth muscle cells, and mesenchymal stem cells. Furthermore, the invention encompasses a visual screening assay method to identify new small-molecule inhibitors that are capable of blocking this specific TERT/STAT5 interaction, providing a direct pathway to develop novel downstream therapeutic compounds.

Applications

- Bioprosthetic Device Coatings\r
- Pharmaceutical Therapeutics for Valve Diseases\r
- Vascular Disease Management\r
- High-Throughput Drug Screening Assays

Advantages

- First-in-Class Disease Modifier\r
- Elimination or Delay of Major Surgeries\r
- Prolonged Device Lifespan\r
- Broad Cellular Protection\r
- High-Throughput Drug Discovery Potential

Invention Readiness

The technology has demonstrated robust in vitro proof of concept. Extensive experimental data has been generated using isolated human aortic valve interstitial cells (AVICs) , human coronary artery smooth muscle cells (CASMCs) , and human mesenchymal stem cells. The data establishes that genetic knockdown of TERT or chemical inhibition of STAT5 (using small molecules like StafiA-1 and StafiB-1) successfully blocks osteogenic transition and dramatically reduces calcium deposition under bone-stimulating conditions. Additionally, comparative studies utilizing wild-type and TERT-knockout mice cells have validated the pathway architecture. Further studies are needed to evaluate the pharmacokinetic profile, safety margins, and optimal delivery methods of these inhibitors in in vivo animal models of cardiovascular calcification prior to clinical evaluation.

IP Status

https://patents.google.com/patent/WO2023205569A1

Related Publication(s)

Small, A. M., Yutzey, K. E., Binstadt, B. A., Voigts Key, K., Bouatia-Naji, N., Milan, D., Aikawa, E., Otto, C. M., & St. Hilaire, C. (2024). Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association. Circulation, 150(6). https://doi.org/10.1161/cir.0000000000001254

Cuevas, R. A., Wong, R., Joolharzadeh, P., Moorhead, W. J., 3rd, Chu, C. C., Callahan, J., 4th, Crane, A., Boufford, C. K., Parise, A. M., Parwal, A., Behzadi, P., & St. Hilaire, C. (2023). Ecto-5′-nucleotidase (Nt5e/CD73)-mediated adenosine signaling attenuates TGFβ-2 induced elastin and cellular contraction. American Journal of Physiology-Cell Physiology, 324(2), C327–C338. https://doi.org/10.1152/ajpcell.00054.2022

Cuevas, R. A., Chu, C. C., Moorhead III, W. J., Wong, R., Sultan, I., & St. Hilaire, C. (2021). Isolation of Human Primary Valve Cells for In vitro Disease Modeling. Journal of Visualized Experiments, 170. https://doi.org/10.3791/62439

","tags":["Coating","Platform Technology","Prosthetics"],"file_number":"05857","collections":[{"key":517,"name":"Cardiometabolic"}],"meta_description":"Inhibits STAT5-TERT interaction to prevent cardiovascular calcification, delaying device degradation and disease progression.","image_url":"","apriori_judge_output":"{\"scores\":{\"novelty\":4.0,\"potential_impact\":4.0,\"readiness\":2.0,\"scalability\":3.0,\"timeliness\":3.0},\"weighted_score\":3.4,\"risks\":[\"TR level is 3 with in vivo proof not yet demonstrated; safety/pharmacokinetics unknown\",\"delivery for coatings vs systemic therapy remains unproven\",\"regulatory pathway for combination coatings/therapeutics unclear\",\"need for in vivo efficacy data in relevant models\"],\"one_sentence_take\":\"High novelty and potential impact with a solid platform concept, but readiness and regulatory/scalability hurdles due to in vivo validation and delivery challenges keep the overall score moderate.\"}","lead_inventor_name":"Cynthia St Hilaire","lead_inventor_dept":"Med-Medicine","technology_type":"Therapeutic Modality","technology_subtype":"Small Molecule","therapeutic_areas":["Musculoskeletal","Cardiovascular"],"therapeutic_indications":["Atherosclerotic disease"],"custom_tags":[],"all_tech_innovators":["Rolando A. Cuevas","Cynthia L. St Hilaire"],"date_submitted":"2021-10-27","technology_readiness_level":"3. Initial proof of concept, in-vivo"},"highlight":{},"matched_queries":null,"score":0.0}