Treatment of vasculopathy with prostacyclin and mesenchymal stem cells
Inventors
Jeffs, Roger • Petersen, Thomas • Ilagan, Roger M. • Wade, Michael
Assignees
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Publication Number
US-12274684-B2
Publication Date
2025-04-15
Expiration Date
Abstract
Provided are methods for treating or preventing vasculopathy in a subject in need thereof, comprising administering to the subject a prostacyclin and a mesenchymal stem cell (MSC) or a MSC-conditioned culture medium or administering to the subject a MSC or a MSC-conditioned culture medium that has treated with prostacyclin. Pharmaceutical compositions suitable for such treatments are also provided.
Core Innovation
The invention concerns a method of preparing a pharmaceutical product by contacting a culture comprising mesenchymal stem cells (MSC) with prostacyclin. After the prostacyclin contact, the MSC or a part of a culture medium that has been in contact with the MSC and contains one or more components of the MSC is isolated for use in the pharmaceutical product.
The prostacyclin includes prostacyclin analogues and prostacyclin receptor agonists, including treprostinil and other PGI2/PGI2-receptor agonists. The disclosure further includes prostacyclin contacting conditions such as a prostacyclin concentration and contacting for at least 24 hours, and selecting MSC components for isolation, including exosomes, microvesicles, microRNA, messenger RNA, non-coding RNA, mitochondria, growth factors, or combinations thereof.
The disclosure also provides for synergy with endothelial progenitor cells (EPC) by optionally including EPC and performing EPC pre-treatment with prostacyclin. In addition, genetic modification is described to enhance eNOS, HMOX1, and/or PTGIS expression, and the resulting product can be combined with carriers such as fibrin glue or hydrogels in pharmaceutical compositions.
Claims Coverage
The document identifies one independent claim covering preparation of a prostacyclin-conditioned MSC-based pharmaceutical product for formulation. The independent claim is supported by dependent claims that add refinements to the prostacyclin contacting step, the identity of isolated MSC components, and optional EPC-related enhancements and nucleic-acid transformation.
Prostacyclin-contacted MSC isolation for a pharmaceutical product
Contacting a culture comprising an MSC with a prostacyclin and thereafter isolating the MSC or a part of a culture medium that has been in contact with the MSC and contains one or more components of the MSC.
Prostacyclin concentration and contacting duration
Contacting the MSC culture with prostacyclin at a prostacyclin concentration and contacting for at least 24 hours.
Isolation of selected MSC components
Isolating a part of a culture medium that has been in contact with the MSC and contains component(s) of the MSC selected from exosomes, microvesicles, microRNA, messenger RNA, non-coding RNA, mitochondria, growth factors, or combinations thereof.
Treprostinil as the prostacyclin
Using treprostinil as the prostacyclin.
EPC nucleic-acid transformation to enhance selected protein activity
Further transforming an EPC with a nucleic acid to increase expression of a selected protein’s biological activity from eNOS, HMOX1, or PTGIS.
Across the independent claim and its dependents, the central claim coverage is the preparation of a pharmaceutical product by prostacyclin contacting of MSC followed by isolation of MSC or MSC-contacted medium containing MSC components, with refinements specifying prostacyclin conditions, the isolated MSC component types, and optional EPC-based enhancement via nucleic-acid transformation targeting eNOS, HMOX1, and/or PTGIS.
Stated Advantages
Supports treating or preventing vasculopathy, including pulmonary arterial hypertension (PAH)/pulmonary hypertension, peripheral vascular disease (PVD)/critical limb ischemia, coronary artery disease, and diabetic vasculopathy.
Induces increased VEGF protein/gene expression in MSC upon treprostinil exposure.
Alters cytokine secretion, including IL-6 upregulation and MCP-1 downregulation.
Increases VEGF-A in MSC-derived exosomes.
Changes exosome-associated microRNAs, including miR-21 and miR-199-3p.
Documented Applications
Treating or preventing vasculopathy, including pulmonary arterial hypertension (PAH)/pulmonary hypertension, peripheral vascular disease (PVD)/critical limb ischemia, coronary artery disease, and diabetic vasculopathy.
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