Compositions and methods for preventing and treating heterotopic ossification and pathologic calcification
Inventors
Assignees
Publication Number
US-10548908-B2
Publication Date
2020-02-04
Expiration Date
2037-09-13
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Abstract
The present invention is directed to compositions and methods for the prevention or treatment of treatment of heterotopic ossification, vascular calcification, or pathologic calcification.
Core Innovation
The invention provides compositions and methods for preventing or treating heterotopic ossification, vascular calcification, or other forms of pathologic calcification by administering combinations of drugs including antagonists of the Hedgehog (Hh) signaling pathway, vitamin D, cholecalciferol or vitamin D analogs, and statins. It focuses on combinations of these agents which, when administered in a co-timely manner, produce greater inhibition of osteogenesis in mesenchymal stem cells than any agent alone, as shown by functional assays measuring reduction of alkaline phosphatase activity and gene expression associated with osteogenic differentiation.
The problem solved by the invention is the lack of generally effective treatments for ectopic bone formation or pathologic calcification conditions, which include heterotopic ossification arising from trauma, surgery, genetic diseases, and other causes. Existing therapies such as NSAIDs and radiation have significant limitations and risks, and current surgical options are often hampered by recurrence or complications. The cellular basis involves mesenchymal progenitor cells differentiating into osteogenic lineages under pathological microenvironments, including inflammation, and there is a recognized need for improved therapeutic methods that address these pathological processes safely and effectively.
The invention also provides preferred dosages and pharmaceutical compositions that enable co-timely administration of these agents, either separately or in a single unit dosage form. It includes specific lists of Hedgehog pathway antagonists, statins, and forms of vitamin D that may be used. The preferred combinations achieve synergistic effects at preventing or treating osteogenesis-related calcification and ossification, potentially reducing individual drug dosages and associated toxicities. Methods for manufacturing such compositions and their use in various administration routes are also described.
Claims Coverage
The patent presents two independent claims covering methods of inhibiting osteogenesis in mesenchymal stem cells and treating heterotopic ossification, vascular or pathologic calcification in patients using combinations of active agents.
Method for inhibiting osteogenesis in mesenchymal stem cells with combinations of agents
Contacting mesenchymal stem cells with either (a) an Hh pathway antagonist combined with either vitamin D (or analog) or a statin, or (b) a combination of an Hh pathway antagonist, vitamin D (or analog), and a statin. The compounds are administered in a co-timely manner at dosages sufficient to effectively inhibit osteogenesis.
Method for treating heterotopic ossification and pathologic calcification with co-timely administration of agent combinations
Administering to a patient (a) a combination of an Hh pathway antagonist with vitamin D (or analog) or a statin; (b) a combination of vitamin D (or analog) and a statin; or (c) a combination of an Hh pathway antagonist, vitamin D (or analog), and a statin, in a co-timely manner at dosages sufficient for therapeutic effectiveness in treating heterotopic ossification, vascular calcification, or other pathologic calcification.
Pharmaceutical compositions comprising combinations of Hedgehog pathway antagonists, vitamin D or analogs, and statins
Unit dosage formulations containing either an Hh pathway antagonist combined with vitamin D (or analog) or a statin, or all three agents together with pharmaceutically acceptable carriers, wherein the amounts present are therapeutically effective for the prevention or treatment of pathological osteogenesis and calcification.
The independent claims cover methods of inhibiting osteogenesis in cells, methods for treating heterotopic or pathologic calcification in patients, and pharmaceutical compositions comprising combinations of Hedgehog pathway antagonists, vitamin D or analogs, and statins. The inventive features specify co-timely administration, preferred agent combinations, therapeutic dosage ranges, and compositions effective in preventing or treating ectopic bone formation and calcification.
Stated Advantages
The combinations of Hedgehog pathway antagonists, vitamin D (or analogs), and statins produce greater inhibition of osteogenesis and heterotopic ossification than any individual component alone, indicating synergistic activity.
The combination therapy allows optimization of safety by reducing the dose of individual agents and thereby minimizing toxicity associated with high doses of drugs.
Co-timely administration of these agents reduces the frequency or severity of side effects relative to administration of single agents alone.
Documented Applications
Prevention or treatment of heterotopic ossification associated with spinal cord damage, traumatic injuries, head or brain injuries, burns, fractures, muscle injuries, and joint replacement surgery.
Treatment of genetic diseases associated with ectopic bone formation or calcification such as progressive osseous heteroplasia, fibrodysplasia ossificans progressiva, and Albright's hereditary osteodystrophy.
Prevention or treatment of vascular calcification relevant to conditions like atherosclerosis and myocardial infarction.
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