Method of and improved composition for treating triterpene-responsive conditions, diseases or disorders
Inventors
Newman, Robert A. • ADDINGTON, Otis C. • Lo, Donald C. • KALTENBACH, LINDA S. • Yang, Peiying
Assignees
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Publication Number
US-11331291-B2
Publication Date
2022-05-17
Expiration Date
Abstract
A method of treating a triterpene-responsive condition, disease or disorder in a subject by administration of an improved triterpene-based composition is provided. An improved triterpene-based composition comprising at least two or at least three triterpenes present at a molar ratio as described herein is also provided.
Core Innovation
The invention relates to an improved triterpene-based therapy for triterpene-responsive conditions by administering a combination of oleanolic acid (OA), ursolic acid (UA), and betulinic acid (BA). The composition controls the molar ratio of OA:UA:BA, and each triterpene is independently selected from the free acid form thereof, salt(s) form thereof, derivative(s) thereof, prodrug(s) thereof and/or combination thereof.
The disclosure addresses the need for improved therapeutic benefit in triterpene-responsive conditions beyond using OA, UA, or BA individually. The balanced molar ratio approach yields synergistic clinical benefit, with reduced cellular toxicity and increased efficacy compared with individual triterpenes when considered on a total-triterpene equimolar basis.
The disclosure attributes the improved benefit to antioxidant response element (ARE) gene induction via Nrf2 signaling, including upregulation of Gcic, Nqo1, Srx, and Hmox1, without excessive overexpression. The document further supports therapeutic-window expansion for optimized mixtures and provides examples including adjusted OA:UA:BA ratio compositions.
Claims Coverage
The relevant independent claims cover methods of treating a triterpene-responsive condition where the condition is cancer, and a brain tumor using a constrained OA:UA:BA molar ratio. Across these independent claims, the main inventive features are the specified OA/UA/BA combination, the permitted triterpene forms, and the defined molar ratio ranges.
Trilevel OA/UA/BA triterpene-based treatment for cancer
A method of treating a triterpene-responsive condition, disease, or disorder comprising administering a triterpene-based composition comprising a combination of a first triterpene oleanolic acid (OA), a second triterpene ursolic acid (UA), and a third triterpene betulinic acid (BA), wherein the triterpene-responsive condition is cancer.
Independently selected free acid/salt/derivative/prodrug triterpene forms
Each triterpene is independently selected at each occurrence from the free acid form thereof, salt(s) form thereof, derivative(s) thereof, prodrug(s) thereof and/or combination thereof.
Constrained OA:UA:BA molar ratio for the OA/UA/BA combination
The molar ratio of OA:UA:BA is selected from the group consisting of about 10:about 1:about 1 and multiple additional specified ranges, including ranges such as about 9-11:about 0.5-1.5:about 0.5-1.5 and about 9-12:about 0.2-2.5:about 0.2-2.5.
Brain tumor OA/UA/BA composition with limited molar ratio range
A method of treating brain tumor comprising administering a therapeutically effective amount of a triterpene-based composition comprising oleanolic acid (or salt thereof), ursolic acid (or salt thereof), and betulinic acid (or salt thereof), wherein the molar ratio of OA to UA to BA is in the range of about 10:about 1:about 1, or about 9-12:about 0.2-2.5:about 0.2-2.5.
Overall, the independent claims require administering OA/UA/BA as a triterpene-based composition with independently selectable free acid/salt/derivative/prodrug forms for cancer and with the OA:UA:BA molar ratio constrained to specified sets or ranges. The brain-tumor independent claim further limits the treated indication to brain tumor and constrains the molar ratio to two defined options.
Stated Advantages
Reduced cellular toxicity.
Increased efficacy.
Synergistic clinical benefit compared with individual triterpenes on a total-triterpene equimolar basis.
Documented Applications
Treating triterpene-responsive conditions where the condition is cancer.
Treating brain tumor, with further narrowing to glioma or glioblastoma.
Therapeutic evaluation in brain slice oxygen-glucose deprivation (OGD) assays, including discussion of neuroprotection.
ARE-related assessment using qPCR and ARE-luciferase reporter assays.
Glioblastoma cell viability assessment in glioblastoma contexts (including reference to U251 and U87).
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