Methods of novel therapeutic candidate identification through gene expression analysis in vascular related diseases
Inventors
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Vascular BioSciencesVascular BioSciences is a biopharmaceutical and medical device company focused on developing targeted therapeutics, minimally invasive interventional devices, and advanced molecular diagnostics for cardiovascular, pulmonary, and inflammatory diseases. The company leverages targeted peptide drug delivery, endovascular tissue sampling, molecular profiling, and bioinformatics to advance personalized medicine for difficult-to-treat diseases. Its operations span California and North Carolina with expertise in biologics, device engineering, and translational research.
Vascular BioSciences is a biopharmaceutical and medical device company focused on developing targeted therapeutics, minimally invasive interventional devices, and advanced molecular diagnostics for cardiovascular, pulmonary, and inflammatory diseases. The company leverages targeted peptide drug delivery, endovascular tissue sampling, molecular profiling, and bioinformatics to advance personalized medicine for difficult-to-treat diseases. Its operations span California and North Carolina with expertise in biologics, device engineering, and translational research.
Publication Number
US-9499816-B2
Publication Date
2016-11-22
Expiration Date
Abstract
The present invention discloses multiple treatment regimens for vascular-related diseases and disorders. The present invention provides for methods of treating vascular-related disorders based on gene expression studies from samples collected from individuals having symptoms of vascular-related disorders. Additionally, methods are disclosed involving diagnostic techniques to focus treatment regimens. Finally, methods of treating vascular-related disorder involving targeting microRNAs are also disclosed.
Core Innovation
The invention identifies dysregulated gene and microRNA signatures in pulmonary arterial hypertension by using minimally invasive serial pulmonary artery/endoarterial biopsies. The approach is implemented in an inducible porcine PAH model and captures stage/time-dependent dysregulation across progression.
Gene expression microarrays are used for whole-genome mRNA and microRNA profiling. The resulting dysregulation is compared against non-diseased control and is analyzed across PAH stages defined by flow rate and blood pressure, including high flow low pressure and high flow high pressure, producing upregulated and downregulated genes and microRNAs.
The patent links particular microRNA expression patterns to pulmonary arterial hypertension stage-specific hemodynamic categories and uses these patterns to define microRNAs to target for treatment. Differentially expressed genes are linked to pharmaceutical agent targets using geneset enrichment and KS ranking to prioritize therapeutic candidates.
Stage-specific treatment selection is enabled by using microRNA dysregulation to select microRNA-targeting agents that inhibit upregulated microRNAs or promote downregulated microRNAs. The listed microRNAs include hsa-miR-520g, hsa-miR-331-5p, hsa-miR-410, hsa-miR-130a, hsa-miR-520d-5p, hsa-miR-6749, hsa-let-7d, hsa-miR-151-5p, hsa-miR-496, hsa-miR-542-5p, hsa-miR-494, hsa-miR-548a-5p, hsa-miR-586, and hsa-let-7f-2.
Claims Coverage
The independent claims cover four methods of treatment for pulmonary arterial hypertension. Across the independent claims, the inventive features specify stage-specific microRNA-targeted treatment selection for high flow and low pressure or high flow and high pressure stages.
Inhibiting upregulated microRNAs for high flow and high pressure PAH
Administering an agent known to inhibit an upregulated microRNA, where the stage of pulmonary arterial hypertension is high flow and high pressure, and where the microRNAs to target are selected from hsa-miR-520g, hsa-miR-331-5p, hsa-miR-410, hsa-miR-130a, and hsa-miR-520d-5p.
Inhibiting upregulated microRNAs for high flow and low pressure PAH
Administering an agent known to inhibit an upregulated microRNA, where the stage of pulmonary arterial hypertension is high flow and low pressure, and where the microRNAs to target are selected from hsa-miR-6749, hsa-let-7d, and hsa-miR-151-5p.
Promoting downregulated microRNAs for high flow and high pressure PAH
Administering an agent known to promote downregulated microRNAs, where the stage of pulmonary arterial hypertension is high flow and high pressure, and where the microRNAs to target are selected from hsa-miR-496, hsa-miR-542-5p, and hsa-miR-494.
Promoting downregulated microRNAs for high flow and low pressure PAH
Administering an agent known to promote downregulated microRNAs, where the stage of pulmonary arterial hypertension is high flow and low pressure, and where the microRNAs to target are selected from hsa-miR-548a-5p, hsa-miR-586, and hsa-let-7f-2.
Overall, the claims provide stage-dependent microRNA-targeted treatment approaches for pulmonary arterial hypertension by pairing inhibition of upregulated microRNAs or promotion of downregulated microRNAs with defined high flow and low pressure or high flow and high pressure stages and corresponding microRNA target sets.
Stated Advantages
Enables stage-specific and personalized therapy selection based on gene dysregulation and microRNA dysregulation.
Prioritizes therapeutic candidates by linking differentially expressed genes to pharmaceutical agent targets using geneset enrichment and KS ranking.
Documented Applications
Minimally invasive serial pulmonary artery/endoarterial biopsies are used to identify dysregulated gene and microRNA signatures in pulmonary arterial hypertension, including stage/time-dependent dysregulation across high flow low pressure and high flow high pressure stages.
MicroRNA and gene expression dysregulation are used to select microRNA-targeting agents for stage-specific pulmonary arterial hypertension treatment.
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