MK-7 Carboxylation Therapy for Pathologic Tissue Calcification
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Solution Overview
Problem
There is a need for new clinical approaches to prevent and/or reverse pathologic calcification in subjects with diabetes, chronic kidney disease, end stage renal disease, and subjects receiving anticoagulant and/or statin therapy, as existing treatments disrupt Vitamin K regulation leading to tissue calcification.
Innovation Solution
Administering high doses of menaquinone-7 (MK-7) and/or menaquinol-7 (MKH2-7) in pharmaceutical compositions to increase Vitamin K-dependent protein carboxylation, thereby preventing, slowing, arresting, or reversing tissue calcification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Vitamin K-dependent proteins are carboxylated to prevent tissue calcification, then calcification prevention is improved, but the complexity of the biochemical regulation system increases
Solution Approach 1:
MK-7 acts as an intermediary substance that mediates the carboxylation of Vitamin K-dependent proteins. By administering this specific form of Vitamin K2, the patent introduces a stable intermediate that efficiently converts to the active reduced form (MKH2-7), which then enables carboxylation of proteins like MGP and osteocalcin, preventing tissue calcification without requiring complex endogenous synthesis pathways.
2Reliability
If high doses of MK-7 are administered to reverse tissue calcification, then treatment effectiveness is improved, but the dosage requirement increases
Solution Approach 1:
The patent utilizes the parameter change from MK-7 (menaquinone-7) to its reduced form MKH2-7 (menaquinol-7) through enzymatic reduction by NADPH-dependent reductase. This parameter transformation enables the compound to become biologically active as a cofactor for gamma-glutamyl carboxylase, allowing effective treatment at specific dosage ranges (at least 2 mg per day) while maintaining treatment effectiveness.
3Reliability
If existing anticoagulant and statin therapies are used, then cardiovascular risk management is improved, but tissue calcification is promoted
Solution Approach 1:
The patent converts the harmful effect of anticoagulant and statin therapies (which deplete functional Vitamin K and promote calcification) into a beneficial outcome by administering high doses of MK-7. This supplementation strategy counteracts the Vitamin K depletion caused by these medications, restoring the carboxylation function of Vitamin K-dependent proteins and preventing calcification while maintaining the cardiovascular benefits of the original therapies.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
MK-7 and MKH2-7 administration significantly increases serum T50 values, enhances the ratio of carboxylated to non-carboxylated Vitamin K-dependent proteins, and reduces markers like D-Dimer and hs-CRP, effectively preventing or reversing tissue calcification.
Implementation Method 1
Vitamin K is an essential enzymatic co-factor that is required for post-translational modifications of Vitamin K-dependent (VKD) proteins. Only the reduced form of MK-7 (namely MKH2-7) functions as a co-factor for the enzyme gamma glutamate carboxylase (GGCX), which catalyzes the carboxylation of Vitamin K-dependent proteins.
Implementation Method 2
under normal conditions MK-7 is reduced to menaquinol-7 (MKH2-7) (a form of Vitamin K hydroquinone) by an NADPH-dependent reductase enzyme or enzymes (e.g., quinone oxidoreductase)
Implementation Method 3
The final step of the Vitamin K cycle requires the enzymatic reduction of Vitamin MK-7 2,3-epoxide back to MK-7 by Vitamin K epoxide reductase complex subunit 1 (VKORC1, also referred to as VKOR)
Implementation Method 4
Uremia can promote the oxidation of Vitamin K hydroquinone (KH2), thereby disrupting the cyclic regeneration of Vitamin K, among other effects.
Data Source
AI summary
The invention provides methods and compositions for preventing or treating (e.g., slowing the progression of, arresting, and/or reversing) tissue calcification in a subject in need thereof and, more particularly, the invention relates to methods of using menaquinone-7 (MK-7) and/or menaquinol-7 (MKH2-7) for preventing or treating (e.g., slowing the progression of, arresting, and/or reversing) tissue calcification in a subject with diabetes, chronic kidney disease, end stage renal failure, or a subject undergoing hemodialysis and/or receiving anticoagulant therapy. The invention further provides methods and compositions for reducing one or more symptoms of chronic obstructive pulmonary disorder (COPD), including using menaquinone-7 (MK-7) and/or menaquinol-7 (MKH2-7), for preventing or treating (e.g., slowing the progression of, arresting, and/or reversing) one or more symptoms of COPD.