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WO2024155570A2 - Utilisation de compositions contenant de la curcumine biodisponible pour le traitement de pseudoachondroplasie - Google Patents

Utilisation de compositions contenant de la curcumine biodisponible pour le traitement de pseudoachondroplasie Download PDF

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WO2024155570A2
WO2024155570A2 PCT/US2024/011583 US2024011583W WO2024155570A2 WO 2024155570 A2 WO2024155570 A2 WO 2024155570A2 US 2024011583 W US2024011583 W US 2024011583W WO 2024155570 A2 WO2024155570 A2 WO 2024155570A2
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reduction
bcc
pain
oil
psach
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WO2024155570A3 (fr
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Karen POSEY
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University of Texas System
University of Texas at Austin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients

Definitions

  • This disclosure relates to methods of treatment of individuals having pseudoachondroplasia (PSACH).
  • PSACH pseudoachondroplasia
  • Cartilage oligomeric matrix protein is a non-collagenous extracellular matrix (ECM) glycoprotein that assists in collagen fibril assembly and binds to multiple ECM proteins enhancing cartilage integrity (Merritt et al., “Unique matrix structure in the rough endoplasmic reticulum cisternae of pseudoachondroplasia chondrocytes,: Am J Pathol 170 (l):293-300 (2007); Thur et al.
  • PSACH pseudoachondroplasia
  • MED multiple epiphyseal dysplasia
  • the present disclosure comprises and provides, in one form thereof, a method of reducing the clinical sequela in an individual diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprising providing a bioavailable curcumin composition (BCC) to the individual, wherein the clinical sequela are selected from the group consisting of decreased femur length, decreased stature, joint pain, joint degeneration, and symptoms of osteoarthritis, and wherein one or more sequela of PSACH are improved.
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • the present disclosure further comprises and provides a method of increasing the stature of a pseudoachondroplasia (PSACH) individual in need thereof, the method comprising providing a composition comprising a bioavailable curcumin composition (BCC).
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • the present disclosure further comprises and provides a method of reducing joint pain in a pseudoachondroplasia (PSACH) patient in need thereof, said method comprising providing a composition comprising a bioavailable curcumin composition (BCC).
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • the present disclosure further comprises and provides a method of reducing cartilage degeneration in an individual diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprising providing a bioavailable curcumin composition (BCC), wherein cartilage degeneration is reduced or delayed.
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • the present disclosure further comprises and provides a method of treating pseudoachondroplasia (PSACH) in an individual in need thereof, comprising providing a bioavailable curcumin composition (BCC).
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • FIGS. 1A-F present an immunohistochemical analysis of the effects of curcumin treatment on COMP protein ER retention according to an exemplary embodiment of the present disclosure showing curcumin treatment reduces mutant- COMP protein ER retention.
  • Control C57BL ⁇ 6
  • MT-COMP MT-COMP growth plates treated with IX (82.3 mg/kg, human equivalent dose assuming a 60 kg human) and 2X (164.6 mg/kg) doses.
  • BCC Bioavailable Curcumin Composition
  • Human-COMP antibody specifically recognizes human mutant-COMP expressed in response to DOX.
  • the MT-COMP mouse is a transgenic model of PSACH which expresses human mutant-COMP in response to DOX administration and wild-type endogenous mouse COMP.
  • Controls show no mutant- COMP protein staining (FIG. 1 A) while untreated MT-COMP growth plate chondrocytes have intracellular retention (FIG. IB), Bioavailable curcumin composition treatment allows some export of mutant-COMP protein (FIG. 1C and FIG. IE) and these chondrocytes have very little mutant-COMP protein signal (FIG. ID and FIG. IF).
  • FIGS. 2A-T present an immunohistochemical analysis of the effects of curcumin treatment on growth plate chondrocyte pathology showing curcumin normalizes growth plate chondrocyte pathology according to an exemplary embodiment of the present application.
  • Growth plates at P28 from control (C57BL ⁇ 6), MT-COMP, and MT-COMP mice treated with IX and 2X Bioavailable curcumin composition doses at P7-P28 are stained with interleukin 6 (IL6), interleukin 10 (IL10), phosphoS6 (pS6), and proliferating cell nuclear antigen (PCNA) antibodies and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining.
  • IL6 interleukin 6
  • IL10 interleukin 10
  • pS6 phosphoS6
  • PCNA proliferating cell nuclear antigen
  • the signal from inflammatory marker IL6 is minimal in controls and MT- COMP IX and 2X BCC (doses of 82.3 and 164.6 mg/kg respectively) treated growth plate chondrocytes compared to MT-COMP untreated controls (FIGS. 2A-D).
  • IL10 is abundant in controls (FIG. 2E) and in BCC treated growth plates (FIG. 2G, FIG. 2H) and absent in the MT- COMP growth plate (FIG. 2F).
  • Autophagy is repressed in MT-COMP growth plates as shown by elevated pS6 immunostaining (measure of mTORCl signaling) compared to controls and MT-COMP treated with BCC (FIGS. 2I-L).
  • FIGS. 3A-O present an immunohistochemical analysis of the effects of BCC treatment on MT-COMP growth plate chondrocyte inflammation, anti-inflammatory, and ER stress markers according to an exemplary embodiment of the present application.
  • Growth plates at P28 from control (C57BL ⁇ 6), MT-COMP, and MT-COMP mice treated with 2X BCC doses at P7-P28 are stained with tumor necrosis alpha (TNFa), interleukin ip (IL1), C/EBP homologous protein (CHOP), midline- 1 (MIDI), and matrix metalloprotease 13 (MMP13) antibodies.
  • TNFa tumor necrosis alpha
  • IL1 interleukin ip
  • C/EBP homologous protein CHOP
  • MIDI midline- 1
  • MMP13 matrix metalloprotease 13
  • FIG. 4 presents a graphical presentation of the effect of curcumin treatment on mouse femoral length.
  • FIG. 5 is a graphical presentation of the effect of curcumin treatment on intracellular MT-COMP protein retention.
  • Intracellular signal from MT-COMP untreated and IX and 2X BCC treatment is quantified using Image J.
  • Intracellular human COMP signal from MT-COMP untreated is set to 100 and both IX and 2X BCC treatment lowered signal to approximately 4.
  • Signal is compared using T-test.
  • *** P ⁇ 0.0005.
  • the results show that BCC dramatically reduces intracellular MT-COMP retention.
  • FIGS. 6A-C present an immunohistochemical analysis of effect of heterozygosity on MT-COMP export according to an exemplary embodiment.
  • Growth plates at P28 from MT-COMP, MT-COMP/mCOMP-/+ and MT-COMP/mCOMP-/- are stained with a human COMP specific antibody (red signal) and DAPI (blue nuclei).
  • the signal from human COMP is primarily intracellular in MT-COMP growth plate chondrocytes (FIG. 6A), extracellular in MT-COMP/mCOMP-/+ and absent in MT-COMP/mCOMP-/-.
  • FIGS 7 is a graphical presentation of the effect of BCC treatment on grooming, a proxy measure of pain. As shown, BCC treatment of MT-COMP mice restores grooming levels to that of control mice.
  • FIG. 8 is a graphical presentation of growth in both PS ACH individuals and non- PSACH individuals. Reproduced from Horton et al. , “Growth curves for height for diastrophic dysplasia, spondyloepiphyseal dysplasia congenita, and pseudoachondroplasia,” Am J. Dis. Child. 136(4):316-9 (1982).
  • FIG. 9 shows grooming outcomes with CurQ+ Treatment.
  • Grooming is a proxy measure for pain and has been used to evaluate CurQ+ regimens.
  • CurQ-i- treatment began at either 1, 4, 6, 8, 12, 16 weeks and was continued till final grooming analysis at 20 weeks.
  • CurQ-i- treatment normalizing grooming scores meaning that there is no significant difference between controls and CurQ-i- treated mutant-COMP mice (MT).
  • Con Control
  • wk weeks
  • MT mutant COMP mice that are a model of pseudoachondroplasia
  • -cont negative control of mutant COMP mice in which the inducer (doxycycline) was not administered
  • *** p ⁇ 0.0005 Koreankal Wallis
  • Fluorescent dye 50 pL was applied on the back of the neck equidistant between ears at time 0, and grooming efficiency was assessed 4 h later in male mice. Animals were imaged and compared to the scoring rubric previously published, with maximal grooming scoring at five. The average grooming scores were compared to controls (Con) at each age using ANOVA and post-hoc Kruskal Wallis. The standard deviation is represented by error bars. [0023] Corresponding reference characters indicate corresponding parts throughout the several views. The examples set out herein illustrate embodiments of the disclosure but should not be construed as limiting the scope of the disclosure in any manner.
  • bioavailable compositions of curcumin provide significant reduction of stress in chondrocytes in the MT-COMP mouse model.
  • the results provide evidence of efficacy for a reduction in symptoms (e.g., sequela) associated with PSACH such as joint pain, osteoarthritis, and impaired growth plate function.
  • Bioavailable compositions of curcumin provide dramatically increased absorption of curcumin (up to 65-fold) over powdered curcumin and turmeric preparations. See Stohs et al.
  • bioavailable curcumin compositions provide significant therapeutic effects in individuals having PSACH and offer potential restoration of normal limb growth, reduction in joint pain, reduction in joint degeneration, and mitigation and reduction of cartilage damage.
  • MT-COMP mice expressing a human mutation to the COMP protein replicate a number of clinical and chondrocyte characteristics of PSACH.
  • a reduction in overall numbers of viable chondrocytes is associated with reductions in chondrocyte proliferation, blockage of chondrocytes autophagy, and an increased number of senescent articular chondrocytes.
  • Joint swelling and inflammation have not been established in the MT-COMP mouse model, but may be obscured by the MT-COMP mouse’s abnormally wide joints. Markers of inflammation are detected.
  • mutant-COMP protein is observed to accumulate intracellularly in growth plate and articular chondrocytes.
  • markers of inflammation are detected, including increased pro-inflammatory factors and decreased antiinflammatory markers.
  • the MT-COMP mouse provides a suitable experimental model to evaluate the effects of treatments, diet, and medicines, to mitigate and reduce the effects of COMP mutation on PSACH individuals in need.
  • the present methods are a significant improvement to the effects observed using high doses of turmeric needed to affect MT-COMP in this mouse model of pseudoachondroplasia (PSACH), shown by Posey et al., to be equivalent to approximately 4g per day for a 26 kg child or 11g per day for a 70 kg adult (Posey et al., 2015).
  • PSACH pseudoachondroplasia
  • turmeric root at 100 mg/kg was shown to reduce zygote implantation by 80% and inhibit pregnancy by 70% in rats (Bhat, et al., 2015).
  • a whole extract of turmeric root at 100-150 mg/kg was shown to have significant anti-coagulant activity (Bhat, et al., 2015).
  • turmeric contains both pro-coagulant and anti-coagulant bioactives that are not curcuminoid in nature.
  • turmeric non-curcuminoid
  • the essential oils of turmeric have been shown to have a wide variety of biological activities including antioxidant, antiinflammatory, and anti-arthritic effects (see Verma and Kumar, 2015), the same effects demonstrated by Posey et al., with turmeric treatment in the mouse model of PSACH (Posey et al., 2015).
  • the data presented herein shows that these PSACH treatment effects are the result of the curcuminoid content of turmeric.
  • BCC curcumin
  • BCCs allow for a total curcuminoid dose of less than 1,000 mg while affording a maximum plasma concentration i'C m j of curcuminoids that is equivalent to having consumed 12,000 mg of 95% curcumin extract powder, a twelve-fold increase in absorption.
  • Some BCCs have even demonstrated 50-fold to 400-fold increases in plasma concentration of curcuminoids (Stohs, et al., 2018).
  • the present studies employ a self-emulsifying formulation strategy though other curcuminoid formulations that achieve high bioavailability without side effect inducing terpenes, proteases, and coagulation modifiers are suitable for use in the methods of the present application.
  • BCCs are self-emulsifying drug delivery systems (SEDDS) or self-microemulsifying drug delivery systems (SMEDDS).
  • SEDDS and SMEDDS commonly utilize a lipid base combined with an amphipathic emulsifier to improve bioavailability to overcome poor aqueous solubility for oral administration of drugs.
  • This strategy is especially effective with lipophilic compounds (i.e. fat soluble, poorly water soluble) such as curcumin.
  • the lipid component of SEDDS/SMEDDS is frequently a vegetable oil or derivatives thereof.
  • Vegetable oils contain mixtures of triglycerides (90 to 95% w/w) but also free fatty acids, phospholipids, and non-saponifiable products such as pigments and sterols or fat-soluble vitamins like tocopherols and carotenoids that act as natural antioxidants. Triglycerides are classified as short ( ⁇ 5 carbons), medium (6-12 carbons) and long chains (>12 carbons). Some typically used vegetable oils include, but are not limited to, castor oil, coconut oil, corn oil, cotton seed oil, grape seed oil, olive oil and sesame oil.
  • the main vegetable oil derivatives are hydrogenated vegetable oils, partial glycerides, polyoxylglycerides (e.g., polyethyleneglycol; PEG), ethoxylated glycerides and esters of edible fatty acids and various alcohols.
  • polyoxylglycerides e.g., polyethyleneglycol; PEG
  • ethoxylated glycerides e.g., esters of edible fatty acids and various alcohols.
  • SEDDS/SMEDDS can utilize a co-solvent to enhance the solubility or facilitate the dispersion of the lipophilic compound in the lipid component.
  • Typical co-solvents used include, but are not limited to, polyethylene glycols, ethanol, propylene glycol, and glycerol.
  • the emulsifier component of the SEDDS/SMEDDS is amphipathic having both hydrophilic (water soluble) and lipophilic (fat soluble) characteristics in order to create emulsions with the lipid component when exposed to the aqueous stomach environment.
  • Typical emulsifiers also known as surfactants
  • the studies presented in the examples of the present application utilize coconut oil as the lipid component and polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/Tween 20) as the emulsifier.
  • the BCC compositions of the examples are commercially available as CurQ+®, available from Stratum Nutrition, Carthage, MO. No co-solvent is used.
  • the resultant mixture is 10-20% curcuminoids, 20-30% coconut oil, and 50-70% Polysorbate 20, with less than 1% Vitamin E as an antioxidant.
  • the present application provides for and includes alternate ratios or concentrations of these constituents and substitution of the lipids, emulsifiers, and antioxidant components or combinations of lipids (e.g., coconut oil - corn oil), emulsifiers (e.g. , Polysorbate 20 + Polysorbate 80), and antioxidants (e.g., Vitamin E + butryatedhydroxy toluene; BHT) to achieve bioavailability and a maximum curcumin plasma level (Cmax) of at least 20 ng/ml within at least 4.0 hours of administration.
  • lipids e.g., coconut oil - corn oil
  • emulsifiers e.g. , Polysorbate 20 + Polysorbate 80
  • antioxidants e.g., Vitamin E + butryatedhydroxy toluene; BHT
  • the present disclosure provides for and includes methods of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprising administering a bioavailable curcumin composition (BCC) to said patient, wherein said sequela are selected from the group consisting of decreased femur length, decreased stature, joint pain, joint degeneration, and symptoms of osteoarthritis, wherein one or more sequela of PSACH are improved.
  • BCC bioavailable curcumin composition
  • the BCC is provided to the individual on a daily, twice daily, or three times daily basis.
  • “bioavailable curcumin compositions” are formulations of curcumin that provide doses of BCC provided to individuals in need that provide a maximum curcumin plasma level (Cmax) of at least 20 ng/ml within at least 4.0 hours of administration. Also included and provided by BCCs are formulations that provide total plasma curcumin having an Area Under the Curve (AUC) of at least 4.0 ng*h/ml over a 6-hour period. In an aspect, BCCs of the present disclosure provide total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • the Cmax of a dose of BCC is between 20 ng/ml and 600 ng/ml. In an aspect, the dose of BCC provides a Cmax of between 30 ng/ml and 100 ng/ml. In another aspect, the dose of BCC provides a Cmax of between 30 ng/ml and 250 ng/ml. In a further aspect, the dose of BCC provides a Cmax of between 100 ng/ml and 250 ng/ml. Also provided for, and included in aspects, are a dose of BCC that provides a Cmax of between 50 ng/ml and 350 ng/ml.
  • the dose of BCC provides a Cmax of between 100 ng/ml and 600 ng/ml. In aspects, the dose of BCC provides a Cmax of at least 50 ng/ml. In a further aspect, the dose of BCC provides a Cmax of at least 100 ng/ml. In yet other aspects, the dose of BCC provides at least 100 ng/ml. In further aspects, the dose of BCC provides a C ma x of at least 200 ng/ml. In an aspect, the dose of BCC provides a Cmax of at least 300 ng/ml. In a further aspect, the dose of BCC provides more than 400 ng/ml up to 600 ng/ml.
  • each dose may be provided once, twice, or three times daily, Cmax levels are determined within at least 4.0 hours of administration.
  • the level of curcuminoids can be determined directly from plasma. In aspects, the level of curcuminoids is determined after enzymatic treatment of a plasma sample.
  • a method of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia comprising providing a dose of BCC wherein said dose provides total curcumin having an Area Under the Curve (AUC) of between 4.0 nanogram hours per milliliter of plasma (ng*hr/ml or ng h/ml) and 3600 ng*h/ml determined over a 6-hour period following a dose of BCC.
  • AUC Area Under the Curve
  • the AUC following a dose of BCC is between 50 ng*hr/ml and 3600 ng h/ml.
  • the AUC following a dose of BCC is between 50 ng*hr/ml and 2500 ng h/ml. In aspects, the AUC following a dose of BCC is between 50 ng*hr/ml and 1500 ng h/ml. In aspects, the AUC following a dose of BCC is between 150 ng*hr/ml and 1000 ng h/ml. In other aspects, the AUC following a dose of BCC is at least 100 ng*hr/ml. In yet other aspects, the AUC following a dose of BCC is at least 150 ng*hr/ml. In other aspects, the AUC following a dose of BCC is at least 300 ng*hr/ml .
  • each dose may be provided once, twice, or three times daily, AUC levels are determined over 6.0 hours of administration.
  • the level of curcuminoids can be determined directly from plasma. In aspects, the level of curcuminoids is determined after enzymatic treatment of a plasma sample.
  • BCC doses comprise less than 1,000 milligrams of total curcuminoids.
  • Suitable exemplary bioavailable preparations are presented in Table 1, reproduced from Stohs et al., “A Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin Formulation with 95% Curcumin: A Randomized, Double-Blind, Crossover Study,” J Am Coll Nutr 37(1);51-59 (2016) and the reference cited therein, hereby incorporated in its entirety.
  • certain bioavailable curcumin preparations achieve Cmax of between 20 and 579 ng/ml within at least 4.0 hours of administration.
  • the raw dose of curcumin present in BCCs vary from 250 mg up to 4,000 mg, the Cmax achieved is not derivable based on the raw dose.
  • the methods of treatment comprise administering a BCC as measured by maximum curcumin plasma levels, not by the initial raw dose of curcumin supplied.
  • Table 1 Normalized Pharmacokinetic Properties of Curcumin preparations.
  • the BCC is a selfemulsifying drug delivery system (SEDDS) or self-microemulsifying drug delivery system (SMEDDS) comprising curcuminoids, a lipid base, and an amphipathic emulsifier.
  • SEDDS selfemulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • additional BCC preparations can be prepared using methods known in the art. See Sarpal et al., Bioavailability can be determined in PSACH individuals, non-PSACH individuals, or using animal models, including but not limited to the MT-COMP mouse system.
  • BCC preparations are a self-emulsifying drug delivery system (SEDDS) or a selfmicroemulsifying drug delivery system (SMEDDS) comprising curcuminoids, a lipid base, and an amphipathic emulsifier.
  • the BCCs of the present disclosure can be selected from CurQ+®, CuroFen, BCM-95, Theracumin, Curofen, BioCurc®, Theracurmin®, Meriva®, Cavacurmin®, CurcuWIN®, or Longvida®.
  • Other compositions provide a Cmax plasma concentration of at least 50 ng/ml after four hours.
  • the BCC is provided to achieve a Cmax of at least 100 ng/ml after four hours.
  • the BCC is provided to achieve a Cmax of at least 150 ng/ml after four hours. Also included are BCCs that provide a C m ax of at least 200 ng/ml after four hours. Other aspects provide for Cmax of between 200 and 600 ng/ml. Since curcumin is generally recognized as safe (See GRAS Notice (GRN) No. 822), BCCs providing higher levels than 600 ng/ml are included and provided for in the present methods.
  • the BCC is selected from CurQ+®, CuroFen, BCM-95, Theracumin®, Curofen, BioCurc®, Theracurmin®, Meriva®, Cavacurmin®, CurcuWIN®, or Longvida®, and the Cmax is at least 20 ng/ml after four hours.
  • BCCs achieve bioavailability using a variety of approaches, all of which are within the scope of the claimed methods.
  • CurcuWIN® composed of 20% curcumin, a hydrophilic carrier, cellulose derivatives and antioxidants provides for a Cmax of 34.9 ng/ml.
  • Cavacurmin® a composition that is a complex of curcumin with y-cyclodextrin provides for a C ma x of 87 ng/ml, more than twice the level of CurcuWIN® at the same raw curcumin dose.
  • Curofen®, a curcumin-galactomannan complex achieves the highest level of bioavailability among the tested compositions.
  • BCCs of the present disclosure are formulated to achieve absorption and accumulation in plasma.
  • Suitable compositions comprise a total curcuminoid concentration of at between 5 and 50% combined with a lipid base.
  • the BCC further comprises an emulsifier, other pharmaceutically acceptable excipients and carriers, or combinations thereof.
  • the lipid base is a vegetable oil or vegetable oil derivative.
  • suitable vegetable oils include, but are not limited to, a vegetable oil selected from coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, or sesame oil.
  • the BCC comprises a vegetable oil derivative.
  • Suitable vegetable oil derivatives include, but are not limited to, hydrogenated vegetable oil, partial glycerides, polyoxylglycerides, ethoxylated glycerides, and polyalcohol esters of edible fatty acids, where said vegetable oil is selected from the group consisting of coconut oil, castor oil, com oil, cotton seed oil, grape seed oil, olive oil and sesame oil.
  • the BCC comprises curcuminoids and an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, Labrasol®, Labrafil® variants, and Gelucire® variants.
  • the BCC comprises a lipid carrier that is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil and sesame oil.
  • the BCCs may comprise micronized curcuminoids plus turmeric oil (BCM-95), phosphatidylcholine from soy lecithin and microcrystalline cellulose (Meriva), complexed with fenugreek-derived galactomannan fiber (CurQfen®), complexed with a hydrophobic carrier, cellulosic derivatives, and natural antioxidants (CurcuWIN®); use of microparticle and surface- controlled colloidal dispersion technology using ghatti gum and glycerin (Theracurmin®); complexed with y-cyclodextrin (Cavacurmin®); and a solid lipid curcumin particle (Longvida®).
  • BCCs that include curcuminoids, a lipid base, an emulsifier, and a co-solvent.
  • Suitable co-solvents include polyethylene glycol, ethanol, propylene glycol, and glycerol.
  • the BCCs comprise curcuminoids, a lipid base, and emulsifier, a co-solvent, and an antioxidant.
  • the antioxidant is vitamin E.
  • the antioxidant is butryatedhydroxytoluene (BHT).
  • BHT butryatedhydroxytoluene
  • antioxidants are included in the BCCs at concentrations of 1% by weight or less.
  • BCCs can comprise a variety of components limited by the ability of the BCC to deliver a maximum curcumin plasma level (Cmax) of at least 20 ng/ml within at least 4.0 hours of administration or provide total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • Cmax maximum curcumin plasma level
  • AUC Area Under the Curve
  • the present methods and disclosure provide for and include, administering doses of BCCs as early as possible to individuals diagnosed with pseudoachondroplasia (PSACH), though certain benefits of BCC administration are achieved at any stage of progression of the disease.
  • a method of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia (PSACH) is initiated when said individual in need exhibits a decrease in linear bone growth, when a waddling gait develops, or both.
  • administration of BCCs is initiated after a positive genetic test for mutations in cartilage oligomeric matrix protein (COMP, also identified as TSP5 and THB5).
  • TSP5 and THB5 cartilage oligomeric matrix protein
  • the methods provide for and include daily doses, not to be limited by theory, it is expected that twice daily or three times daily administration will achieve enhanced benefit. More specifically, in certain aspects, the dosages can be adjusted to achieve and maintain a plasma level of curcumin of at least 20 ng/ml.
  • the BCC is provided immediately before, during, or after
  • the present disclosure provides for and includes methods of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprising providing a bioavailable curcumin composition (BCC) to said patient, wherein said sequela are selected from the group consisting of decreased femur length, decreased stature, joint pain, joint degeneration, and symptoms of osteoarthritis, wherein one or more sequela of PSACH are improved.
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • the method provides for a reduction in clinical sequela is an improvement or increase in long bone length or an increase in stature.
  • the length of the femur is increased in the individual or the stature is increased relative to an untreated PSACH individual.
  • the methods provide for an improvement in stature that is an increase in height and a reduction in the standard deviation from the normal in the height compared to non-PSACH individuals of the same age.
  • PSACH Public Access to Corning Accord
  • MED-EDM1 Early-onset joint degeneration. The methods of the present specification are initiated as soon as possible after a diagnosis of PSACH and are intended to continue indefinitely to reduce the lifelong clinical sequala of PSACH.
  • curcumin can have chondroprotective effects that slow/inhibit joint degeneration Chen et al., “Curcumin ameliorates IL- 1 beta- induced apoptosis by activating autophagy and inhibiting the NF-kappa B signaling pathway in rat primary articular chondrocytes.” Cell Biol Int, 2021 , 45:976-988, (2021), Li etal., “Curcumin Inhibits Apoptosis of Chondrocytes through Activation ERK1/2 Signaling Pathways Induced Autophagy.” Nutrients, 9:4, (2017), Yao et al., “Curcumin-Alleviated Osteoarthritic Progression in Rats Fed a High-Fat Diet by Inhibiting Apoptosis and Activating Autophagy via Modulation of Micro
  • Dwarfism is short stature that results from a genetic or medical condition, in the present application, dwarfism is a sequalae of PSACH due to mutations in the COMP protein.
  • Dwarfism is generally defined as an adult height of 4 feet 10 inches (147 centimeters) or less. See world-wide-web at mayoclinic.org/diseases-conditions/dwarfism/symptoms-causes/syc- 20371969.
  • dwarfism heights are more than 2 standard deviations away from mean of the population and, like stature generally, is sexually dimorphic. Height is determined by a range of factors from genetic to diet, disease and exercise.
  • the increase in stature is determined by comparing the height to a similar situated population. In aspects, the increase in stature or height is compared to an ethnically matched population.
  • the mean male height is 69.3 inches (176 cm) with a standard deviation of 2.8 inches (7.11 cm) (a range of about 63.5 to 75.1 inches or 161 cm to 191 cm).
  • the mean female height is 64 inches (162.6 cm) with a standard deviation of 2.8 inches (7.1 1 cm) (a range of about 58.2 to 69.8 inches or 148 cm to 177 cm).
  • the present methods provide for an increase in height (e.g. , a reduction in clinical sequala) relative to the mean. Increases in height can be observed as an increase in height, a reduction in the standard deviation from the normal height, or both compared to non-PSACH individuals of the same age.
  • the standard deviation from the norm is increased by 0.5.
  • the standard deviation from normal height is reduced by 1.0.
  • the increase in height comprises a reduction to less than 2.0 standard deviations from the mean.
  • the standard deviation from the mean is reduced between 0.1 and 1.5 relative to the normal height.
  • the improvements are determined after six months of administration. In aspects and for maximal results, the administration comprises administering a BCC three times daily.
  • the improvement in height and stature depends on the age at the time of administration is initiated.
  • the present methods provide for, and include early administration, beginning as early as 2 years old, when PSACH becomes clinically evident, and continues through puberty.
  • improvements in stature can be obtained and observed only during the normal periods of long bone growth with the growth in an average male completed by 20 years and completed by 16 years in females.
  • benefits and improvements to PSACH individuals persist (e.g., reductions in joint pain, joint degeneration, and symptoms of osteoarthritis)
  • the degree of improvement in height and stature is generally limited to ages between 2 and 20 years.
  • PSACH and non-PSACH groups are readily distinguished at an early age and each group presents considerable internal variation. See FIG.7, showing improvements in the height and stature naturally take time to become evident and show significant variation. Some methods exist where an individual with PSACH can be measured after 6 months of administration. In aspects, the improvements are observed after 1 year, 1.5 years, 2 years, or more of BCC administrations. Larger improvements may be expected in younger children as the long bones grow faster in young children compared to teens.
  • the methods provide for an extension of the growth period in a PSACH individual through age 8 up through the normal growth phase observed in non-PSACH individuals when administration of BCCs is initiated at ages 2 to 5 and continued through age 8 and later.
  • the methods of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprise providing a bioavailable curcumin composition (BCC) to said patient, wherein joint degeneration is reduced.
  • BCC bioavailable curcumin composition
  • reductions in joint degeneration are determined after six months of administering BCC.
  • the reductions in joint degeneration are observed after 1 year, 1.5 years, 2 years, or more of BCC administrations.
  • joint degeneration can be monitored using methods known in the art, for example magnetic resonance imaging (MRI), radiography, and CT-scans and other higher resolution scans.
  • CTX-II C-telopeptide
  • ELISA enzyme-linked immunosorbent assay
  • administering BCC to a PSACH individual reduces the plasma levels of the biomarker CTX-II after thirty (30) days.
  • a reduction in the biomarker CTX-II is a reduction of at least 10% relative to the level of CTX-II prior to administration of a BCC.
  • a reduction in the biomarker CTX-II is a reduction of at least 20% relative to the level of CTX-II prior to administration of a BCC.
  • a reduction in the biomarker CTX-II is a reduction of at least 30% relative to the level of CTX-II prior to administration of a BCC.
  • the present disclosure provides for and includes methods of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprising providing a bioavailable curcumin composition (BCC) to said patient, wherein the symptoms of osteoarthritis are reduced.
  • the methods further provide for reductions in associated problems such as pain medication management.
  • the reductions of symptoms are provided after at least 30 days of once daily, twice daily, or thrice daily administration of BCC to the individual.
  • reductions of symptoms of atherosclerosis are obtained after at least 60 days of once daily, twice daily, or thrice daily administration of BCC to the individual.
  • reductions of symptoms of atherosclerosis are obtained after at least 90 days of once daily, twice daily, or thrice daily administration of BCC to the individual.
  • End-stage joint disease in PSACH is largely indistinguishable from end-stage osteoarthritic joint degeneration. Joint degeneration and pain necessitate premature replacement of hips and often knees, elbows, and shoulders. Hip replacements typically occur around age 29 - 32 years, and persistent joint pain compromises the quality of life in PSACH. See McKeand et al., (1996), and Unger and Hecht, “Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments,” American Journal of Medical Genetics 106(4):244 (2001).
  • Osteoarthritis including PSACH presents with a variety of clinical symptoms that can be improved or mitigated by the methods provided in this application, including, but not limited to, joint pain, pain with walking, joint stiffness (particularly joint stiffness in the morning), joint degeneration, inflammation, and reductions in joint movement.
  • the present methods provide for BCC administration to individuals having one or more of these clinical conditions in the mounts presented above.
  • the present methods provide for reductions in the use of medications. Pain management is an important component of administration plans medication logs.
  • the methods provide for reductions in pain medication compared to individuals administered a BCC compared to the individual prior to administration or the average individuals having PSACH. Decreases in pain medication use may present within one, two, or three weeks from the initiation of administration of a BCC to an individual.
  • administering BCCs reduces the pain associated with osteoarthritis and accordingly reduces the need for pain medication in treated PSACH individuals.
  • the use of pain medications following BCC administration is reduced by 10% measured over a period of one week compared to the use of pain medications prior to BCC administration.
  • the use of pain medications following BCC administration is reduced by 10% measured over a period of one month compared to the use of pain medications prior to BCC administration.
  • the dose, frequency, or both of over-the-counter (OTC) pain medications used per month is reduced.
  • the dose, frequency, or both of a prescription pain medication is reduced in a PSACH individual administered a BCC according to the present methods compared to an untreated PSACH individual, or the PSCAH individual prior to BCC administration.
  • the dose, frequency, or both of over-the-counter (OTC) pain medications used per week is reduced.
  • the dose, frequency, or both of a prescription pain medication is reduced in a PSACH individual administered a BCC according to the present methods compared to an untreated PSACH individual, or the PSCAH individual prior to BCC administration.
  • the OTC pain medication is acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), or a topical pain reliever comprising aspirin, lidocaine, capsaicin or other medication.
  • administration of a BCC to a PSACH individual reduces the does, frequency, or both of a prescription pain reliever.
  • the prescription pain reliever is an antidepressant such as Elavil®, a tricyclic or a serotonin-norepinephrine reuptake inhibitor (SNRI), such as Effexor® and Cymbalta®.
  • the prescription pain reliever is gabapentin or pregabalin.
  • the reduction in pain reliever use is a reduction in the dosage or frequency of an opioid.
  • the reduction in pain reliever use is a reduction in the dosage or frequency of a steroid, for example a corticosteroid, such as prednisone.
  • reductions in the symptoms of osteoarthritis can be observed after six months of at least daily administration of a BCC according to the present application.
  • biomarkers such as CTX-II discussed above
  • a reduction of joint degeneration a symptom of osteoarthritis can be detected as little as seven (7) days following once, twice, or thrice daily administration of a BCC.
  • a reduction in osteoarthritis symptoms comprises a reduction in the detection of the CTX-II biomarker in a treated PSACH individual at 30 days by at least 10%.
  • Joint pain is a major clinical complication in PSACH beginning in childhood. Not to be limited by theory, joint pain is believed to be caused by an underlying chondrocyte inflammation in the growth plate. See Posey et al., (2015), Posey and Hecht, “Novel therapeutic interventions for pseudoachondroplasia,” Bone (2017), and Gamble et al., “Pseudoachondroplasia and painful sequelae, Am J Med Genet A 167(11):2618-22 (2015). Joint pain continues into adulthood and reflects osteoarthritic changes exacerbated by extreme joint laxity. See McKeand et al., “Natural history study of pseudoachondroplasia,” American Journal of Medical Genetics 63(2):406-410 (1996). In certain aspects, joint pain is associated with, but not limited to osteoarthritis.
  • the present disclosure provides for and includes methods for reducing joint pain in a pseudoachondroplasia (PSACH) individual in need thereof comprising providing a bioavailable curcumin composition (BCC) to said individual, thereby reducing joint pain in said PSACH individual.
  • BCC bioavailable curcumin composition
  • the BCC is provided to said individual to achieve a maximum curcumin plasma level (Cmax) of at least 20 ng/ml within at least 4.0 hours of administration.
  • the method for reducing joint pain includes providing an amount of BCC to achieve Cmax of between 10 and 579 ng/ml within at least 4.0 hours of administration.
  • the BCC is provided to achieve a Cmax of at least 100 ng/ml after four hours.
  • the BCC is provided to achieve a Cmax of at least 150 ng/ml after four hours. Also included are BCCs that provide a Cmax of at least 200 ng/ml after four hours. Other aspects provide for Cmax of between 200 and 600 ng/ml. Also included and provided for in a method for reducing joint pain in a pseudoachondroplasia (PSACH) individual in need thereof, is providing BCC to achieve a total curcumin having an Area Under the Curve (AUC) of at least 4.0 ng*h/ml over a 6-hour period. In an aspect, the BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period. In an aspect, the BCC is provided daily. In other aspects, the BCC is provided twice daily. Also included are methods wherein the BCC is provided three times daily.
  • administering reduces the pain, including pain associated with osteoarthritis, wherein said reduction in pain is a reduction in pain reporting on one or more pain measures known in the art, including but not limited to pain logs, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Medical Outcomes Study Short-Form 36 (SF-36) scale, the Visual Analogue Scale (VAS).
  • WOMAC Western Ontario and McMaster Universities Osteoarthritis Index
  • SF-36 Medical Outcomes Study Short-Form 36
  • VAS Visual Analogue Scale
  • a reduction in joint pain refers to at least a 30% improvement over baseline measurement.
  • the reduction in pain is a reduction in a VAS score that is at least a 10% improvement over pre- administration baseline or compared to an untreated population. In aspects, the reduction in pain is a reduction in a VAS score that is at least a 15% improvement over pre-administration baseline or compared to an untreated population. In aspects, the reduction in pain is a reduction in a VAS score that is at least a 20% improvement over preadministration baseline or compared to an untreated population. In aspects, the reduction in pain is a reduction in a VAS score that is at least a 30% improvement over pre-administration baseline or compared to an untreated population. In some aspects, the reduction in joint pain comprises a reduction in pain perception by the individual of 40% on the Visual Analog Scale (VAS).
  • VAS Visual Analog Scale
  • the reduction in joint pain comprises a reduction in pain perception by the individual of 50% on the Visual Analog Scale (VAS). In some aspects, the reduction in joint pain comprises a reduction in pain perception by the individual of 60% on the Visual Analog Scale (VAS). In an aspect, the reduction in joint pain in a BCC treated individual in need comprises an average reduction in pain perception of at least 0.5 points on a 10-point ordinal scale when measured after a week. In an aspect, the reduction in joint pain in a BCC treated individual in need comprises an average reduction in pain perception of at least 0.5 points on a 10-point ordinal scale when measured after two weeks.
  • the reduction in joint pain in a BCC treated individual in need comprises an average reduction in pain perception of at least 0.5 points on a 10-point ordinal scale when measured after a month. In an aspect, the reduction in joint pain in a BCC treated individual in need comprises an average reduction in pain perception of at least 1.0 point on a 10-point ordinal scale when measured after a week. In an aspect, the reduction in joint pain in a BCC treated individual in need comprises an average reduction in pain perception of at least 1.0 point on a 10-point ordinal scale when measured after two weeks. In an aspect, the reduction in joint pain in a BCC treated individual in need comprises an average reduction in pain perception of at least 1.0 point on a 10-point ordinal scale when measured after a month.
  • the methods provide for reductions in pain as measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) or the Medical Outcomes Study Short-Form 36 (SF-36) scales.
  • the WOMAC and SF-36 methods are useful for assessing pain with functional activities. (Quantifying the pain experience in hip and knee osteoarthritis Pain Res Manag. 2010 Jul-Aug; 15(4): 224-228.)
  • the WOMAC index is improved at least 10% relative to baseline.
  • pain as measured using the SF-36 scale is reduced at least 10% relative to baseline.
  • the WOMAC index is improved at least 15% relative to baseline.
  • pain as measured using the SF-36 scale is reduced at least 15% relative to baseline. In aspects of the present application, the WOMAC index is improved at least 20% relative to baseline. In an aspect, pain as measured using the SF-36 scale is reduced at least 20% relative to baseline. In aspects of the present application, the WOMAC index is improved at least 30% relative to baseline. In an aspect, pain as measured using the SF-36 scale is reduced at least 30% relative to baseline.
  • the present application provides for a method of reducing pain comprising providing a dose of a BCC, the reductions in pain are reductions in one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales.
  • the reductions are determined after 30 days of once daily, twice daily, or thrice daily administration of a BCC.
  • the BCC is provided at meal time.
  • the methods provide for at least a 10% reduction in one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales after three months of daily administration.
  • the methods provide for at least a 15% reduction in one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales after three months of daily administration. In aspects, the methods provide for at least a 20% reduction in one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales after three months of daily administration. In aspects, the methods provide for at least a 30% reduction in one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales after three months of daily administration.
  • Pain intensity (PI) can be measured using one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales, and a reduction in PI is at least a 10% reduction over the baseline. Pain intensity (PI) can be measured using one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales, and a reduction in PI is at least a 15% reduction over the baseline.
  • Pain intensity (PI) can be measured using one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales, and a reduction in PI is at least a 20% reduction over the baseline. Pain intensity (PI) can be measured using one or more of the VAS, WOMAC, SF-36, Wong-Baker, or HQRL scales, and a reduction in PI is at least a 30% reduction over the baseline. In aspects, the reduction in PI is a reduction in PI during walking. Pain intensity during walking can be assessed on an 11- point numerical rating scale (NRS), with 0: No Pain - 10: Worst Pain You Can Imagine, at 0, 3, 6, 9, 12, 15, 18, and 20 min.
  • NRS 11- point numerical rating scale
  • a reduction in PI during walking is a reduction in the time-weighted average (TWA) from baseline PI on Day 3 after two self-paced walks.
  • TWA time-weighted average
  • the present disclosure provides for and includes methods for reducing joint pain in a pseudoachondroplasia (PSACH) individual in need thereof comprising providing a bioavailable curcumin composition (BCC) to said individual, thereby reducing joint pain in said PSACH individual, wherein the reduction in pain is a reduction in a Knee Injury and Osteoarthritic Score (KOOS).
  • the KOOS is an extension of the WOMAC osteoarthritis index developed to evaluate short and long-term symptoms in individuals with knee injury and osteoarthritis.
  • the KOOS holds five separately scored subscales: Pain, other Symptoms, Function in daily living (ADL), Function in Sport and Adventure (Sport/Rec), and knee-related Quality of Life (QOL).
  • the KOOS is improved by at least 10% compared to baseline. In aspect, the KOOS is improved by at least 20% compared to baseline. As used herein, improvements in KOOS are provided after at least 30 days of administration of a BCC at least once daily. As used herein, improvements in KOOS are provided after at least 60 days of administration of a BCC at least once daily. In aspects, the BCC is provided twice daily or three times daily.
  • the present disclosure provides for and includes methods for reducing joint stiffness in a pseudoachondroplasia (PSACH) individual in need thereof comprising providing a bioavailable curcumin composition (BCC) to said individual, thereby reducing joint stiffness in said PSACH individual.
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • joint stiffness is reduced by at least 10% compared to baseline.
  • joint stiffness is reduced by at least 20% compared to baseline.
  • reductions in joint stiffness are provided after at least 30 days of administration of a BCC at least once daily.
  • reductions in joint stiffness are provided after at least 60 days of administration of a BCC at least once daily.
  • the BCC is provided twice daily or three times daily.
  • the present specification provides for and includes a method of preventing cartilage degeneration in an individual diagnosed with pseudoachondroplasia (PSACH) comprising providing a bioavailable curcumin composition (BCC) wherein said BCC provides a maximum curcumin plasma level (Cmax) of at least 20 ng/ml within at least 4.0 hours of administration.
  • PSACH pseudoachondroplasia
  • the present disclosure provides for, and includes methods to prevent joint degeneration in a pseudoachondroplasia (PSACH) individual in need thereof comprising providing a bioavailable curcumin composition (BCC) to said individual, thereby preventing or halting joint degeneration in said PSACH individual.
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • PSACH pathology is not limited to the growth plate, premature joint degeneration is the most debilitating and painful complication associated with this COMPopathy Posey and Hecht “The role of cartilage oligomeric matrix protein (COMP) in skeletal disease.” Curr Drug Targets, 9:869-77 (2008), Unger and Hecht, “Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments.” American Journal of Medical Genetics 2001, 106: 244 (2001), Posey et al., 2014, Posey et al., “Novel therapeutic interventions for pseudoachondroplasia.” Bone, 102:60-68 (2017), Hecht et al., “Primary Osteoarthritis Early Joint Degeneration Induced by Endoplasmic Reticulum Stress Is Mitigated by Resveratrol.” Am J Pathol, 191:1624-1637 (2021), Coustry et al., “Mutant cartilage oligomeric matrix
  • the methods to prevent joint degeneration in a PSACH individual comprises providing a BCC to said individual and obtaining a maximum curcumin plasma level (C max ) of at least 20 ng/ml within at least 4.0 hours of administration.
  • the method for preventing joint degeneration includes providing an amount of BCC to achieve C max of between 10 and 579 ng/ml within at least 4.0 hours of administration.
  • the BCC is provided to achieve a Cmax of at least 100 ng/ml after four hours.
  • the BCC is provided to achieve a C max of at least 150 ng/ml after four hours.
  • BCCs that provide a C max of at least 200 ng/ml after four hours.
  • C max of between 200 and 600 ng/ml.
  • BCC also included and provided for a method for preventing joint degeneration in a pseudoachondroplasia (PSACH) individual in need thereof, is providing BCC to achieve a total curcumin having an Area Under the Curve (AUC) of at least 4.0 ng*h/ml over a 6-hour period.
  • AUC Area Under the Curve
  • the BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • the BCC is provided daily.
  • the BCC is provided twice daily. Also included are methods wherein the BCC is provided three times daily.
  • the present specification provides for and includes methods of reducing cartilage degeneration in a pseudoachondroplasia (PSACH) individual in need thereof, said method comprising providing a composition comprising a bioavailable curcumin composition (BCC) to said individual at least once daily, thereby reducing cartilage degeneration.
  • the BCC provides total curcumin having an Area Under the Curve (AUC) of at least 4.0 ngUi/ml over a 6-hour period.
  • AUC Area Under the Curve
  • AUC Area Under the Curve
  • the method to reduce joint pain includes providing a BCC to an individual diagnosed with pseudoachondroplasia (PSACH), wherein the maximum curcumin plasma level (Cmax) is at least 20 ng/ml within at least 4.0 hours of administration.
  • the method provides for an amount of BCC to achieve Cmax of between 10 and 579 ng/ml within at least 4.0 hours of administration.
  • the BCC is provided to achieve a Cmax of at least 100 ng/ml after four hours.
  • the BCC is provided to achieve a Cmax of at least 150 ng/ml after four hours.
  • BCCs that provide a Cmax of at least 200 ng/ml after four hours.
  • Other aspects provide for Cmax of between 200 and 600 ng/ml.
  • the BCC is provided daily.
  • the BCC is provided twice daily.
  • a method of reducing cartilage degeneration provides for, and includes, identifying a pseudoachondroplasia (PSACH) individual as early as possible.
  • PSACH pseudoachondroplasia
  • the method comprises performing a genetic test for mutations in the cartilage oligomeric matrix protein (COMP) gene, identifying a PSACH individual, and providing a BCC to said individual at least once daily, wherein the maximum curcumin plasma level (Cmax) is at least 20 ng/ml within at least 4.0 hours of administration.
  • the method comprises reviewing a genetic test of the COMP gene, identifying a PSACH individual and initiating administration at least once daily with a BCC wherein the maximum curcumin plasma level (Cmax) is at least 20 ng/ml within at least 4.0 hours of administration.
  • the method provides for an amount of BCC to achieve Cmax of between 10 and 579 ng/ml within at least 4.0 hours of administration.
  • the BCC is provided to achieve a C ma x of at least 100 ng/ml after four hours. In yet another aspect, the BCC is provided to achieve a Cmax of at least 150 ng/ml after four hours. Also included are BCCs that provide a Cmax of at least 200 ng/ml after four hours. Other aspects provide for Cmax of between 200 and 600 ng/ml.
  • a method of reducing cartilage degeneration in a pseudoachondroplasia (PSACH) individual in need thereof comprising identifying a PSACH individual in need of administration that exhibits a decrease in linear bone growth, when a waddling gait develops, or both.
  • PSACH pseudoachondroplasia
  • the present disclosure provides for and includes methods of treatment of pseudoachondroplasia (PSACH), a severe dwarfing condition comprising providing a bioavailable curcumin composition (BCC) to a person in need thereof.
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • Pseudoachondroplasia PSACH, OMIM: 17770
  • PSACH, OMIM: 17770 is an autosomal dominant osteochondrodysplasia characterized by disproportionate short stature, deformity of the lower limbs, brachydactyly, loose joints, and ligamentous laxity. Vertebral anomalies, present in childhood, usually resolve with age, but osteoarthritis is progressive and severe.
  • PSACH is caused by heterozygous mutations in the gene encoding cartilage oligomeric matrix protein (COMP; OMIM: 600310, Gene ID: 1311) on chromosome 19p 13.
  • COMP cartilage oligomeric matrix protein
  • the COMP gene is also involved in the disorder Multiple Epiphyseal Dysplasia- 1 (EDM1; OMIM: 132400) which has similar, but milder phenotype.
  • EDM1 Multiple Epiphyseal Dysplasia- 1
  • PSACH and EDM1 comprise a clinical spectrum with phenotypic overlap between mild forms of PSACH and EDM1.
  • the current working model of PSACH growth plate chondrocyte pathology is a self-perpetuating loop initiated by the retention of mutant-COMP in the endoplasmic reticulum (ER) of chondrocytes that stimulates severe and unrelenting cellular stress resulting in chondrocyte death.
  • the loss of growth plate chondrocytes is understood to decrease the pool of chondrocytes that produce matrix for long bone growth and cartilage resurfacing of the joint and the dead/dying chondrocytes may release inflammatory molecules that compromise viability and function of the remaining growth plate and articular chondrocytes.
  • curcumin benefits are inhibition of 1) mTORCl resulting in autophagy stimulation Li et al., “Curcumin Inhibits Apoptosis of Chondrocytes through Activation ERK1/2 Signaling Pathways Induced Autophagy.” Nutrients, 9:4, (2017), Yao et al., “Curcumin-Alleviated Osteoarthritic Progression in Rats Fed a High-Fat Diet by Inhibiting Apoptosis and Activating Autophagy via Modulation of MicroRNA-34a.” J Inflamm Res, 14:2317-2331, (2021), Kakiuchi et al., “Pharmacological inhibition of mTORCl but not mT0RC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction.” Osteoarthritis Cartilage, 27:965-976, (2019), Xiao
  • BCC administration decreases IL6, ILip, and TNFa inflammation, autophagy blockage, chondrocyte death, and increases proliferation and IL10 (anti-inflammatory). Additionally, the anti-inflammatory effect of BCC that is mediated through multiple cytokines suggests that BCC is an effective method to address pain in PSACH that has been associated with inflammation Unger and Hecht, “Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments.” American Journal of Medical Genetics 2001, 106: 244 (2001), Posey et al., “Role of TSP-5/COMP in pseudoachondroplasia.” Int J Biochem and Cell Bio, 36:1005-12, (2004), Kidd et al.
  • BCC preserved growth plate chondrocyte viability and proliferation. BCC restored IL10 levels, which controls MMP13 cartilage degradation and decreased pro- inflammatory molecules IL6, ILip, and TNFa that drive high levels of chondrocyte stress. ILip and TNFa attract eosinophils previously shown to be part of the mutant-COMP protein pathology.
  • the results presented here support methods that target the pathologic processes due to MT-COMP early in life to prevent childhood joint pain, potentially restore some lost limb growth
  • the methods further provide for reducing joint pain in an individual diagnosed with pseudoachondroplasia (PSACH), for preventing cartilage degeneration in an individual diagnosed with pseudoachondroplasia (PSACH), even after the end of the growth plate period of development.
  • PSACH pseudoachondroplasia
  • PSACH cartilage degeneration in an individual diagnosed with pseudoachondroplasia
  • the present specification provides for and includes methods for treating an individual diagnosed with pseudoachondroplasia (PSACH), comprising providing a bioavailable curcumin composition to an individual diagnosed with pseudoachondroplasia (PSACH), wherein the BCC provides total curcumin having an Area Under the Curve (AUC) of at least 4.0 ng*h/ml over a 6-hour period.
  • the BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • the method provides a BCC to an individual diagnosed with pseudoachondroplasia (PSACH), wherein the maximum curcumin plasma level (Cmax) is at least 20 ng/ml within at least 4.0 hours of administration.
  • the methods provide for an amount of BCC to achieve Cmax of between 10 and 579 ng/ml within at least 4.0 hours of administration.
  • the BCC is provided to achieve a C max of at least 100 ng/ml after four hours.
  • the BCC is provided to achieve a Cmax of at least 150 ng/ml after four hours.
  • BCCs that provide a Cmax of at least 200 ng/ml after four hours.
  • Other aspects provide for Cmax of between 200 and 600 ng/ml.
  • the BCC is provided daily.
  • the BCC is provided twice daily.
  • PSACH pseudoachondroplasia
  • methods of treating PSACH are continued indefinitely to provide relief of PSACH symptoms such as elevated levels of inflammation.
  • the method provides reductions in inflammation. As provided herein, reduced levels of inflammation can be measured using methods known in the art.
  • the method for treating an individual diagnosed with pseudoachondroplasia comprises providing a BCC to said individual and reducing the level of one or more inflammatory marker or pro-inflammatory cytokines.
  • the administration results in the reduction in IL-6 expression.
  • the administration provides for a reduction in markers of inflammation selected from the group consisting of tumor necrosis factor (TNF, also commonly known as TNF-alpha, Gene ID:7124), interleukin 1 beta (IL1B, Gene ID:2533) , DNA damage inducible transcript 3 (DDIT3, also known as CHOP, Gene ID: 1649), midline 1 (MIDI, Gene ID:4322), matrix metallopeptidase 13 (MMP13, Gene ID: 4322), and eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also known as PERK, Gene ID:9451).
  • TNF tumor necrosis factor
  • IL1B interleukin 1 beta
  • DDIT3 DNA damage inducible transcript 3
  • DDIT3 DNA damage inducible transcript 3
  • DDIT3 DNA damage inducible transcript 3
  • DDIT3 DNA damage inducible transcript 3
  • DDIT3 DNA damage inducible transcript 3
  • DDIT3 DNA damage inducible transcript
  • the method for treating an individual diagnosed with pseudoachondroplasia comprises providing a BCC to said individual and comprises a reduction in levels of markers of inflammation in the plasma of said individual selected from the group consisting of TNFa, IL- 1 p, IL-6, CRP, CRPM, C3M.
  • the treating with a BCC comprises a reduction in levels of markers of inflammation in the plasma of said individual selected from the group consisting of microRNA miR-1307-5p, miR- 140-3p, miR-181a-3p, miR-221-5p, miR-4326, miR-4443, and miR-99a-5p.
  • the administration with a BCC comprises a reduction in levels of microRNAs from the miR-320 family.
  • said reduction in microRNAs from the miR-320 family comprises a reduction in one or more miR-320b, miR-320c, miR-320d, and miR-320e .
  • the markers of inflammation in the plasma are reduced to within one standard deviation of normal levels in an age matched population without PSACH.
  • the treating of a PSACH individual with a BCC comprises a reduction in IncRNA selected from the group consisting of MAF1-AS1, MALAT1, and Patched 1 pseudogene (LOC 100287846). See Rocha and Ali (2022).
  • the present application provides for, and includes a method of treating individuals with PSACH resulting in restoration of long bone growth.
  • administration is initiated upon a genetic or clinical diagnosis of PSACH and continues during the development of long bong growth, for example throughout adolescence through adulthood. While the methods provide for further improvements in individual clinical symptoms and would generally be continued (e.g., to reduce joint damage, prevent cartilage degeneration), further improvements in long bone growth are not expected following the end of the normal growth phase.
  • the increase in long bone length is an increase in femur length.
  • Femur lengths and other long bone development can be monitored using methods known in the art, for example by orthoroentgenography and DXA (dual energy X-ray absorptiometry). See, for example, Chinappen-Horsley et al. , A Method for Determining Skeletal Lengths from DXA Images,” BMC Musculoskeletal Disorders 8:113 (2008).
  • the methods provide for measuring improvements in a PSACH individual in need thereof though comparison to normal individuals. Methods of assessing normal and abnormal growth are known in the art. See Legler and Rose, “Assessment of Abnormal Growth Curves,” Am. Fam. Physician. 58(1): 153-158 (1998).
  • the method provides for an increase in femur length wherein the femur is restored to between 50 and 100% of the length of a non-PSACH individual.
  • femur is restored to at least 95% of the length of a non-PSACH individual.
  • the femur is restored to at least 85% of the length of a non-PSACH individual.
  • Other aspects provide for restored femur length that is at least 60% of the length of a non-PSACH individual.
  • the femur length is restored between 60 and 95%, 70 and 95%, and 80 to 95%.
  • the method provides for an increase in long bone length wherein the long bone is restored to between 50 and 100% of the length of a non-PSACH individual.
  • the long bone is restored to at least 95% of the length of a non-PSACH individual.
  • the long bone is restored to at least 85% of the length of a non-PSACH individual.
  • Other aspects provide for restored long bone length that is at least 60% of the length of a non- PSACH individual.
  • the long bone length is restored between 60 and 95%, 70 and 95%, and 80 to 95%.
  • the method further provides for an increase in long bone length wherein the long bone length in said PSACH individual is restored to within 1 standard deviation of the normal long bone length of non-PSACH individuals of the same age.
  • the method provides for an increase in long bone length wherein the long bone length in said PSACH individual is restored to within 1 standard deviation of the normal long bone length of a population of non- PSACH individuals of the same age and same ethnic group. See, for example, Choi et al. , “Distribution of Lengths of the Normal Femur and Tibia in Korean Children from Three to Sixteen Years of Age,” J.
  • the population of non-PSACH individuals for comparison can be selected based on age and ethnic group and can further be defined geographically. By geographic selection, differences due to diet and standard of living are minimized allowing the improvements compared to the non-PSACH population to be more easily quantified.
  • the restoration of long bone length is determined relative to a nationally representative sample. Methods for determining a nationally representative sample are known to those of skill in the art. See Kuczmarski et al., “2000 CDC growth charts for the United States: Methods and development,” National Center for Health Statistics.
  • the improvement is thought to result from BCC reduction in MT-COMP growth plate chondrocyte stress.
  • the 2X BCC dosage fully restores femur length while IX dosage recovers 60% of lost femoralfemoral length.
  • the present disclosure provides for a method of restoring limb growth in an individual having PSACH comprising providing a bioavailable curcumin composition (BCC) to said individual at least once daily during the period of bone growth.
  • BCC bioavailable curcumin composition
  • administration to restore limb growth is initiated upon a genetic or clinical diagnosis of PSACH and continues during the development of long bong growth, for example throughout adolescence through adulthood.
  • the present disclosure provides for, and includes, initiating administrations as long as the growth plate remains open, typically through the end of puberty (about 13 to 15 for girls and 15 to 17 for boys).
  • the benefits of providing BCC to individual with PSACH such as reducing joint pain, reducing or preventing joint degeneration, preventing cartilage degeneration, persist after the closure of the growth plate, persists.
  • the present specification provides for and includes the use of a BCC for the manufacture of a medicament for the treatment of an individual diagnosed with pseudoachondroplasia (PSACH) and in need thereof, wherein clinical sequela selected from the group consisting of decreased femur length, decreased stature, joint pain, joint degeneration, and symptoms of osteoarthritis, and wherein one or more sequela of PSACH are improved.
  • PSACH pseudoachondroplasia
  • the present specification provides for and includes the use of a BCC for the manufacture of a medicament for the treatment of reduced stature of a pseudoachondroplasia (PSACH) individual in need thereof, the method comprising providing a composition comprising a bioavailable curcumin composition (BCC) to said individual.
  • PSACH pseudoachondroplasia
  • the present specification provides for and includes the use of a BCC for the manufacture of a medicament for a method of reducing joint pain in a pseudoachondroplasia (PSACH) patient in need thereof, said method comprising providing a composition comprising a bioavailable curcumin composition (BCC).
  • BCC bioavailable curcumin composition
  • the present specification provides for and includes the use of a BCC for the manufacture of a medicament for a method of treating pseudoachondroplasia (PSACH) in an individual in need thereof, comprising providing a bioavailable curcumin composition (BCC).
  • PSACH pseudoachondroplasia
  • the present specification provides for and includes the use of a BCC for the manufacture of a medicament for the treatment of an individual diagnosed with pseudoachondroplasia (PSACH) and in need thereof, wherein clinical sequela selected from the group consisting of decreased femur length, decreased stature, joint pain, joint degeneration, and symptoms of osteoarthritis, and wherein one or more sequela of PSACH are improved.
  • PSACH pseudoachondroplasia
  • PSACH pseudoachondroplasia
  • PSACH pseudoachondroplasia
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • the term “about” refers to ⁇ 10 %.
  • the term “one or more sequela of PSACH that are improved” refers to clinal improvement following administration with a BCC. Improvements include reductions in intracellular COMP in growth plate chondrocytes, inflammation and markers of inflammation, reductions of pro-inflammatory cytokines, and increases in expression of antiinflammatory growth factors.
  • the term “reduction” means that the value is reduced relative to the value determined in a similarly situated non-PSACH individual or non-PSACH individual population.
  • the term “providing” means administering an oral BCC to an individual having PSACH at a dose that provides at least a maximum curcumin plasma level (Cniax) of at least 20 ng/ml within at least 4.0 hours of administration.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • Embodiment 1 A method of reducing the clinical sequela in an individual diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprising providing a bioavailable curcumin composition (BCC) to said individual, wherein said sequela are selected from the group consisting of decreased femur length, decreased stature, joint pain, joint degeneration, and symptoms of osteoarthritis, wherein one or more sequela of PSACH are improved.
  • BCC bioavailable curcumin composition
  • Embodiment 2 The method of embodiment 1, wherein said BCC provides a maximum curcumin plasma level (Cma ) of at least 20 ng/ml within at least 4.0 hours of administration.
  • Cma curcumin plasma level
  • Embodiment 3 The method of embodiment 2, where said Cmax is at least 50 ng/ml.
  • Embodiment 4 The method of embodiment 1, wherein said BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • AUC Area Under the Curve
  • Embodiment 5 The method of any one of embodiments 1 to 4, wherein said Cmax is measured directly or following enzymatic treatment of a plasma sample.
  • Embodiment 6 The method of any one of embodiments 1 to 5, wherein said BCC is provided to said individual in need thereof at least once daily, twice daily, or three times daily.
  • Embodiment 7 The method of any one of embodiments 1 to 6, wherein the BCC comprises a dose of less than 1,000 milligrams of total curcuminoids.
  • Embodiment 8 The method of any one of embodiment 1 to 7, wherein said BCC is a self-emulsifying drug delivery system (SEDDS) or self-microemulsifying drug delivery system (SMEDDS) comprising curcuminoids, a lipid base, and an amphipathic emulsifier.
  • SEDDS self-emulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • Embodiment 9 The method of any one of embodiments 1 to 8, said curcuminoids comprise a total curcuminoid concentration of 5 to 50% by weight; and said lipid base is a vegetable oil or vegetable oil derivative.
  • Embodiment 10 The method of any one of embodiments 1 to 9, wherein said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 11 The method of any one of embodiments 1 to 9, wherein said lipid base is a vegetable oil derivative comprising hydrogenated vegetable oil, partial glycerides, polyoxylglycerides, ethoxylated glycerides, and poly alcohol esters of edible fatty acids, where said vegetable oil is selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil and sesame oil, and combinations thereof.
  • Embodiment 12 The method of any one of embodiments 1 to 9, wherein said amphipathic emulsifier is an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 80, polysorbate 85, and combinations thereof.
  • said amphipathic emulsifier is an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 80, polysorbate 85, and combinations thereof.
  • Embodiment 13 The method of any one of embodiments 1 to 9, wherein said composition further comprises a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • Embodiment 14 The method of any one of embodiments 1 to 10, wherein said lipid base comprises coconut oil and said emulsifier comprises polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/Tween 20).
  • Embodiment 15 The method of e any one of embodiments 1 to embodiment 9, wherein said curcuminoid concentration is 10 to 20%, said coconut oil concentration is 20 to 30%, and said emulsifier is 50 to 70% polysorbate 20.
  • Embodiment 16 The method of any one of embodiments 1 to 15, wherein said BCC further comprises an antioxidant.
  • Embodiment 17 The method of any one of embodiments 1 to 16, wherein said antioxidant is vitamin E or bu try atedhydroxy toluene (BHT).
  • said antioxidant is vitamin E or bu try atedhydroxy toluene (BHT).
  • Embodiment 18 The method of any one of embodiments 1 to 16, wherein said antioxidant is vitamin E at a concentration of less than 1 % by weight.
  • Embodiment 19 The method of any one of embodiments 1 to 18, wherein said method of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia (PSACH) is initiated when said patient in need exhibits a decrease in linear bone growth, when a waddling gait develops, or both.
  • PSACH pseudoachondroplasia
  • Embodiment 20 The method of any one of embodiments 1 to 18, wherein said method of reducing the clinical sequela of individuals diagnosed with pseudoachondroplasia (PSACH)is initiated after a positive genetic test for mutations in cartilage oligomeric matrix protein (COMP).
  • PSACH pseudoachondroplasia
  • Embodiment 21 The method of any one of embodiments 1 to 18, wherein said sequela is an increase in is an increase in femur length or an increase in stature in said PSACH individual in need thereof.
  • Embodiment 22 The method of embodiment 21 , wherein said femur length or stature is improved femur length or stature relative to an untreated PSACH individual.
  • Embodiment 23 The method of embodiment 21, wherein said improvement in stature comprises an increase in height and a reduction in the standard deviation from the normal in the height compared to non-PSACH individuals of the same age.
  • Embodiment 24 The method of embodiment 23, wherein said decrease in the standard deviation is a reduction by 0.5.
  • Embodiment 25 The method of embodiment 23, wherein said decrease in the standard deviation is reduction by 1.0.
  • Embodiment 26 The method of embodiment 23, wherein said decrease in the standard deviation is a reduction to less than 2.0 standard deviations from the mean.
  • Embodiment 27 The method of embodiments 23, wherein the decrease in standard deviation is measured after six months of treatment.
  • Embodiment 28 The method of embodiments 27, wherein the decrease in standard deviation is measured after six months of treatment and said BCC is provided three times daily.
  • Embodiment 29 The method of embodiment 23, wherein said improved femur length or stature is observed after the age of eight (8) in PSACH individuals administered BCCs.
  • Embodiment 30 The method of embodiment 23, wherein said non-PSACH individuals are ethnically matched.
  • Embodiment 31 The method of any one of embodiments 1 to 18, wherein said one or more sequela of PSACH that are improved comprises a reduction in joint degeneration as measured by at least a 10% reduction in the cartilage degradation biomarker, CTX-II, compared to before treatment.
  • Embodiment 32 The method of embodiment 31, wherein said reduction in joint degeneration is measured after six months of said providing of said BCC.
  • Embodiment 33 The method of embodiment 31 or 32, wherein said reduction in joint degeneration is measured systemically in serum or urine or directly in synovial aspirations.
  • Embodiment 34 The method of any one of embodiments 1 to 18, wherein said one or more sequela of PSACH that are improved comprises a reduction in symptoms of osteoarthritis.
  • Embodiment 35 The method of embodiment 34, wherein said reduction in symptoms is measured after six months of said providing said BCC.
  • Embodiment 36 The method of embodiment 35, wherein said BCC is provided twice daily.
  • Embodiment 37 The method of embodiment 34, wherein said reduction in symptoms is a reduction in the use of pain medication.
  • Embodiment 38 The method of embodiment 37, wherein said pain medication is an over- the-counter pain medication or a prescription pain medication.
  • Embodiment 39 The method of embodiment 34, wherein said reduction in symptoms is at least a 10% reduction in pain reporting information on the visual analogue scale (VAS) after at least 30 days of daily administration.
  • VAS visual analogue scale
  • Embodiment 40 The method of embodiment 34, wherein said reduction in symptoms is at least a 10% reduction in pain on the Wong-Baker scale after at least 30 days of daily administration.
  • Embodiment 41 The method of embodiment 34, wherein said reduction in symptoms is at least a 10% reduction in pain on the WOMAC scale after at least 30 days of daily administration.
  • Embodiment 42 The method of embodiment 34, wherein said reduction in symptoms is at least a 10% reduction in pain on the SF-36 scale after at least 30 days of daily administration.
  • Embodiment 43 The method of embodiment 34, wherein said reduction in symptoms is at least a 10% reduction in pain on the HQRL scale after at least 30 days of daily administration.
  • Embodiment 44 The method of embodiment 34, wherein said reduction in symptoms is a reduction in pain with walking after at least 30 days of daily administration.
  • Embodiment 45 The method of embodiment 44, wherein said reduction in pain with walking is a reduction in pain intensity (PI) compared to a baseline PI without treatment with said BCC.
  • PI pain intensity
  • Embodiment 46 The method of embodiment 44, wherein said reduction in pain with walking is a reduction in the time to moderate pain (TTMP) compared to a baseline measurement without treatment with said BCC.
  • TTMP time to moderate pain
  • Embodiment 47 The method of embodiment 34, wherein said reduction in symptoms is a reduction in a Knee Injury and Osteoarthritic Score (KOOS).
  • KOOS Knee Injury and Osteoarthritic Score
  • Embodiment 48 The method of embodiment 34, wherein said reduction in symptoms is an improvement in knee biomechanical markers.
  • Embodiment 49 The method of embodiment 34, wherein said reduction in symptoms is a reduction in morning stiffness.
  • Embodiment 50 The method of any one of embodiments 1 to 18, wherein said one or more sequela of PSACH that are reduced is inflammation.
  • Embodiment 51 A method of increasing the stature of a pseudoachondroplasia (PSACH) patient in need thereof, said method comprising providing a composition comprising a bioavailable curcumin composition (BCC).
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • Embodiment 52 The method of embodiment 51 , wherein said BCC provides a maximum curcumin plasma level (Cmax) of at least 20 ng/ml within at least 4.0 hours of administration.
  • Cmax maximum curcumin plasma level
  • Embodiment 53 The method of embodiment 51 or 52, wherein said Cmax is measured directly or following enzymatic treatment of a plasma sample.
  • Embodiment 54 The method of any one of embodiments 51 to 53, wherein said BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • AUC Area Under the Curve
  • Embodiment 55 The method of any one of embodiments 1 to 51 to 54, wherein said BCC is provided to said individual in need thereof at least once daily, twice daily, or three times daily.
  • Embodiment 56 The method any one of embodiments 51 to 55, wherein the BCC comprises a dose of less than 1,000 milligrams of total curcuminoids.
  • Embodiment 57 The method of any one of embodiments 51 to 55, wherein said BCC is a self-emulsifying drug delivery system (SEDDS) or self-microemulsifying drug delivery system (SMEDDS) comprising curcuminoids, a lipid base, and an amphipathic emulsifier.
  • SEDDS self-emulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • Embodiment 58 The method of any one of embodiments 51 to 57, wherein said curcuminoids comprise a total curcuminoid concentration of 5 to 50% by weight; and said lipid base is a vegetable oil or vegetable oil derivative.
  • Embodiment 59 The method of any one of embodiments 51 to 58, wherein said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 60 The method of any one of embodiments 51 to 59, wherein said lipid base is a vegetable oil derivative comprising hydrogenated vegetable oil, partial glycerides, polyoxylglycerides, ethoxylated glycerides, and poly alcohol esters of edible fatty acids, where said vegetable oil is selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 61 The method of any one of embodiments 51 to 60, wherein said amphipathic emulsifier is an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 80, polysorbate 85, and combinations thereof.
  • Embodiment 62 The method of any one of embodiments 51 to 61, wherein said composition further comprises a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • Embodiment 63 The method of any one of embodiments 51 to 62, wherein said lipid base comprises coconut oil and said emulsifier comprises polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/Tween 20).
  • Embodiment 64 The method of any one of embodiments 51 to 63, wherein said curcuminoid concentration is 10 to 20%, said coconut oil concentration is 20 to 30%, and said emulsifier is 50 to 70% polysorbate 20.
  • Embodiment 65 The method of any one of embodiments 51 to 64, wherein said BCC further comprises an antioxidant.
  • Embodiment 66 The method of any one of embodiments 51 to 64, wherein said antioxidant is vitamin E or butryatedhydroxytoluene (BHT).
  • said antioxidant is vitamin E or butryatedhydroxytoluene (BHT).
  • Embodiment 67 The method of embodiment 66, wherein said antioxidant is vitamin E at a concentration of less than 1% by weight.
  • Embodiment 68 The method of any one of embodiments 51 to 67, wherein said method of increasing the stature is initiated when said patient in need exhibits a decrease in linear bone growth, when a waddling gait develops, or both.
  • Embodiment 69 The method of any one of embodiments 51 to 68, wherein said method of increasing the stature of individuals diagnosed with pseudoachondroplasia (PSACH) is initiated after a positive genetic test for mutations in cartilage oligomeric matrix protein (COMP).
  • Embodiment 70 The method of any one of embodiments 51 to 69, wherein said improvement in stature comprises an increase in height and a reduction in the standard deviation from the normal in the height compared to non-PSACH individuals of the same age.
  • Embodiment 71 The method of any one of embodiments 51 to 70, wherein said decrease in the standard deviation is a reduction by 0.5.
  • Embodiment 72 The method of any one of embodiments 51 to 70, wherein said decrease in the standard deviation is reduction by 1.0.
  • Embodiment 73 The method of any one of embodiments 51 to 70, wherein said decrease in the standard deviation is a reduction to less than 2.0 standard deviations from the mean.
  • Embodiment 74 The method of any one of embodiments 51 to 73, wherein the decrease in standard deviation is measured after six months of treatment.
  • Embodiment 75 The method of any one of embodiments 51 to 70, wherein the decrease in standard deviation is measured after six months of treatment and said BCC is provided three times daily.
  • Embodiment 76 The method of any one of embodiments 51 to 70, wherein said improved femur length or stature is observed after the age of eight (8) in PSACH individuals administered BCCs.
  • Embodiment 77 The method of any one of embodiments 51 to 70, wherein said non- PSACH individuals are ethnically matched.
  • Embodiment 78 A method of reducing joint pain in a pseudoachondroplasia (PSACH) patient in need thereof, said method comprising providing a composition comprising a bioavailable curcumin composition (BCC).
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • Embodiment 79 The method of embodiment 78, wherein said BCC provides a maximum curcumin plasma level (C ma x) of at least 20 ng/ml within at least 4.0 hours of administration.
  • Embodiment 80 The method of embodiment 79, where said Cmax is at least 50 ng/ml.
  • Embodiment 81 The method of embodiment 78, wherein said BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • Embodiment 82 The method of any one of embodiments 78 to 81, wherein said C ma x is measured directly or following enzymatic treatment of a plasma sample.
  • Embodiment 83 The method of any one of embodiments 78 to 81, wherein said BCC is provided to said individual in need thereof at least once daily, twice daily, or three times daily.
  • Embodiment 84 The method of any one of embodiments 78 to 83, wherein the BCC comprises a dose of less than 1,000 milligrams of total curcuminoids.
  • Embodiment 85 The method of any one of embodiments 78 to 84, wherein said BCC is a self-emulsifying drug delivery system (SEDDS) or self-microemulsifying drug delivery system (SMEDDS) comprising curcuminoids, a lipid base, and an amphipathic emulsifier.
  • SEDDS self-emulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • Embodiment 86 The method of any one of embodiments 78 to 85, wherein said curcuminoids comprise a total curcuminoid concentration of 5 to 50% by weight; and said lipid base is a vegetable oil or vegetable oil derivative.
  • Embodiment 87 The method of any one of embodiments 78 to 86, wherein said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 88 The method of any one of embodiments 78 to 86, wherein said lipid base is a vegetable oil derivative comprising hydrogenated vegetable oil, partial glycerides, polyoxylglycerides, ethoxylated glycerides, and polyalcohol esters of edible fatty acids, where said vegetable oil is selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 89 The method of any one of embodiments 78 to 86, wherein said amphipathic emulsifier is an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 80, polysorbate 85, and combinations thereof.
  • Embodiment 90 The method of any one of embodiments 78 to 86, wherein said composition further comprises a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • Embodiment 91 The method of any one of embodiments 78 to 88, wherein said lipid base comprises coconut oil and said emulsifier comprises polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/Tween 20).
  • Embodiment 92 The method of any one of embodiments 78 to 86, wherein said curcuminoid concentration is 10 to 20%, said coconut oil concentration is 20 to 30%, and said emulsifier is 50 to 70% polysorbate 20.
  • Embodiment 93 The method of any one of embodiments 78 to 92, wherein said BCC further comprises an antioxidant.
  • Embodiment 94 The method of any one of embodiments 78 to 93, wherein said antioxidant is vitamin E or butryatedhydroxytoluene (BHT).
  • said antioxidant is vitamin E or butryatedhydroxytoluene (BHT).
  • Embodiment 95 The method of any one of embodiments 78 to 93, wherein said antioxidant is vitamin E at a concentration of less than 1 % by weight.
  • Embodiment 96 The method of any one of embodiments 78 to 86, wherein said method of reducing joint pain of individuals diagnosed with pseudoachondroplasia (PSACH) is initiated when said patient in need exhibits a decrease in linear bone growth, when a waddling gait develops, or both.
  • PSACH pseudoachondroplasia
  • Embodiment 97 The method of any one of embodiments 78 to 86, wherein said method of reducing joint pain of individuals diagnosed with pseudoachondroplasia (PSACH) is initiated after a positive genetic test for mutations in cartilage oligomeric matrix protein (COMP).
  • PSACH pseudoachondroplasia
  • Embodiment 98 The method of any one of embodiments 78 to 97, wherein said reduction in joint pain is measured after six months of said providing said BCC.
  • Embodiment 99 The method of any one of embodiments 78 to 98, wherein said BCC is provided twice daily.
  • Embodiment 100 The method of any one of embodiments 78 to 99, wherein said reduction joint pain further includes a reduction in the use of pain medication.
  • Embodiment 101 The method of any one of embodiments 78 to 100, wherein said pain medication is an over-the-counter pain medication or a prescription pain medication.
  • Embodiment 102 The method of any one of embodiments 78 to 101, wherein said reduction in joint pain is at least a 10% reduction in pain reporting information on the visual analogue scale (VAS) after at least 30 days of daily administration.
  • VAS visual analogue scale
  • Embodiment 103 The method of any one of embodiments 78 to 102, wherein said reduction in joint pain is at least a 10% reduction in pain on the Wong-Baker scale after at least 30 days of daily administration.
  • Embodiment 104 The method of any one of embodiments 78 to 103, wherein said reduction in joint pain is at least a 10% reduction in pain on the WOMAC scale after at least 30 days of daily administration.
  • Embodiment 105 The method of any one of embodiments 78 to 104, wherein said reduction in joint pain is at least a 10% reduction in pain on the SF-36 scale after at least 30 days of daily administration.
  • Embodiment 106 The method of any one of embodiments 78 to 105, wherein said reduction in joint pain is at least a 10% reduction in pain on the HQRL scale after at least 30 days of daily administration.
  • Embodiment 107 The method of any one of embodiments 78 tol06, wherein said reduction in joint pain is a reduction in pain with walking after at least 30 days of daily administration.
  • Embodiment 108 The method of any one of embodiments 78 tol07, wherein said reduction in joint pain a reduction in pain intensity (PI) with walking compared to a baseline PI without treatment with said BCC.
  • PI pain intensity
  • Embodiment 109 The method of any one of embodiments 78 to 108, wherein said reduction in PI with walking is a reduction in the time to moderate pain (TTMP) compared to a baseline measurement without treatment with said BCC.
  • TTMP time to moderate pain
  • Embodiment 110 The method of any one of embodiments 78 to 109, wherein said reduction in joint pain is a reduction in a Knee Injury and Osteoarthritic Score (KOOS).
  • KOOS Knee Injury and Osteoarthritic Score
  • Embodiment 111 The method of any one of embodiments 78 tol lO, wherein said reduction in joint pain is an improvement in knee biomechanical markers.
  • Embodiment 112. The method of any one of embodiments 78 to 111, wherein said reduction in joint pain further includes a reduction in morning stiffness.
  • Embodiment 113 The method of any one of embodiments 78 to 112, wherein said reduction in joint pain comprises a reduction in HQRL or pain log.
  • Embodiment 114 The method of any one of embodiments 78 to 113, wherein said reduction in joint pain comprises a reduction in pain perception by the individual of at least 10% on the Visual Analog Scale (VAS).
  • VAS Visual Analog Scale
  • Embodiment 115 The method of any one of embodiments 78 to 114, wherein said reduction in joint pain comprises an average reduction in pain perception of at least 0.5 points on a 10-point ordinal scale when measured after a week.
  • Embodiment 116 A method of reducing cartilage degeneration in an individual diagnosed with pseudoachondroplasia (PSACH) and in need thereof, comprising providing a bioavailable curcumin composition (BCC), wherein cartilage degeneration is reduced or delayed.
  • PSACH pseudoachondroplasia
  • BCC bioavailable curcumin composition
  • Embodiment 117 The method of embodiment 116, wherein said BCC provides a maximum curcumin plasma level (C ma x) of at least 20 ng/ml within at least 4.0 hours of administration.
  • C ma x maximum curcumin plasma level
  • Embodiment 118 The method of embodiment 117, where said Cmax is at least 50 ng/ml.
  • Embodiment 119 The method of embodiment 116, wherein said BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • AUC Area Under the Curve
  • Embodiment 120 The method of any one of embodiments 116 to 117, wherein said Cmax is measured directly or following enzymatic treatment of a plasma sample.
  • Embodiment 121 The method of any one of embodiments 116 to 120, wherein the BCC comprises a dose of less than 1,000 milligrams of total curcuminoids.
  • Embodiment 122 The method of any one of embodiments 116 to 121 BCC is provided to said individual in need thereof at least once daily, twice daily, or three times daily.
  • Embodiment 123 The method of any one of embodiments 116 to 122, wherein said BCC is a self-emulsifying drug delivery system (SEDDS) or self-microemulsifying drug delivery system (SMEDDS) comprising curcuminoids, a lipid base, and an amphipathic emulsifier.
  • SEDDS self-emulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • Embodiment 124 The method of any one of embodiments 116 to 123, wherein said curcuminoids comprise a total curcuminoid concentration of 5 to 50% by weight; and said lipid base is a vegetable oil or vegetable oil derivative.
  • Embodiment 125 The method of embodiment 124, wherein said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, com oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 126 The method of any one of embodiments 116 to 124, wherein said lipid base is a vegetable oil derivative comprising hydrogenated vegetable oil, partial glycerides, polyoxylglycerides, ethoxylated glycerides, and polyalcohol esters of edible fatty acids, where said vegetable oil is selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 127 The method of any one of embodiments 116 to 124, wherein said amphipathic emulsifier is an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 80, polysorbate 85, and combinations thereof.
  • Embodiment 128 The method of any one of embodiments 116 to 124, wherein said composition further comprises a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • Embodiment 129 The method of any one of embodiments 116 to 124, wherein said lipid base comprises coconut oil and said emulsifier comprises polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/Tween 20).
  • Embodiment 130 The method of any one of embodiments 116 to 124, wherein said curcuminoid concentration is 10 to 20%, said coconut oil concentration is 20 to 30%, and said emulsifier is 50 to 70% polysorbate 20.
  • Embodiment 131 The method of embodiment 130, wherein said BCC further comprises an antioxidant.
  • Embodiment 132. The method of embodiment 131, wherein said antioxidant is vitamin E or butryatedhydroxytoluene (BHT).
  • Embodiment 133 The method of embodiment 131, wherein said antioxidant is vitamin E at a concentration of less than 1 % by weight.
  • Embodiment 134 The method of any one of embodiments 116 to 133, wherein said method of reducing cartilage degeneration in individuals diagnosed with pseudoachondroplasia (PSACH) is initiated when said patient in need exhibits a decrease in linear bone growth, when a waddling gait develops, or both.
  • PSACH pseudoachondroplasia
  • Embodiment 135. The method of any one of embodiments 116 to 134, wherein said method of reducing cartilage degeneration in individuals diagnosed with pseudoachondroplasia (PSACH)is initiated after a positive genetic test for mutations in cartilage oligomeric matrix protein (COMP).
  • PSACH pseudoachondroplasia
  • Embodiment 136 The method of any one of embodiments 116 to 135, wherein said reduction in joint degeneration is measured after six months of said providing of said BCC.
  • Embodiment 137 The method of any one of embodiments 116 to 136, wherein said BCC is provided twice daily.
  • Embodiment 138 The method of any one of embodiments 116 to 137, further comprising a reduction in inflammation.
  • Embodiment 139 The method of any one of embodiments 116 to 138, wherein said reduction in cartilage degeneration is reduction in rate of cartilage degeneration as measured by MRI.
  • Embodiment 140 The method of embodiment 139, MRI measurement is a comparison to a period prior to treatment with said BCC.
  • Embodiment 141 The method of any one of embodiments 116 to 140, wherein said reduction in cartilage degeneration is reduction in serum levels of extracellular matrix degradation products of type II collagen.
  • Embodiment 142 The method of embodiment 141, wherein said Type II collagen degradation product is the C-telopeptide (CTX-II).
  • Embodiment 143 A method of treating pseudoachondroplasia (PSACH) in an individual in need thereof, comprising providing a bioavailable curcumin composition (BCC).
  • PSACH pseudoachondroplasia
  • Embodiment 144 The method of embodiment 143, wherein said treating comprises increasing the femur length, increasing stature, decreasing joint pain, reducing joint degeneration, reducing the symptoms of osteoarthritis, and combinations thereof.
  • Embodiment 145 The method of embodiment 143, wherein said BCC provides a maximum curcumin plasma level (Cmax) of at least 20 ng/ml within at least 4.0 hours of administration.
  • Cmax maximum curcumin plasma level
  • Embodiment 146 The method of embodiment 145, where said Cmax is at least 50 ng/ml.
  • Embodiment 147 The method of embodiment 143, wherein said BCC provides total curcumin having an Area Under the Curve (AUC) of at least 50.0 ng*h/ml over a 6-hour period.
  • AUC Area Under the Curve
  • Embodiment 148 The method of any one of embodiments 143 to 147, wherein said Cmax is measured directly or following enzymatic treatment of a plasma sample.
  • Embodiment 149 The method of any one of embodiments 143 to 148, wherein said BCC is provided to said individual in need thereof at least once daily, twice daily, or three times daily.
  • Embodiment 150 The method of any one of embodiments 143 to 149, wherein the BCC comprises a dose of less than 1,000 milligrams of total curcuminoids.
  • Embodiment 151 The method of any one of embodiments 143 to 150, wherein said BCC is a self-emulsifying drug delivery system (SEDDS) or self-microemulsifying drug delivery system (SMEDDS) comprising curcuminoids, a lipid base, and an amphipathic emulsifier.
  • SEDDS self-emulsifying drug delivery system
  • SMEDDS self-microemulsifying drug delivery system
  • Embodiment 152 The method of embodiment 151, wherein said curcuminoids comprise a total curcuminoid concentration of 5 to 50% by weight; and said lipid base is a vegetable oil or vegetable oil derivative.
  • Embodiment 153 The method of any one of embodiments 143 to 152, wherein said lipid base is a vegetable oil selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 154 The method of any one of embodiments 143 to 152, wherein said lipid base is a vegetable oil derivative comprising hydrogenated vegetable oil, partial glycerides, polyoxylglycerides, ethoxylated glycerides, and polyalcohol esters of edible fatty acids, where said vegetable oil is selected from the group consisting of coconut oil, castor oil, corn oil, cotton seed oil, grape seed oil, olive oil, sesame oil, and combinations thereof.
  • Embodiment 155 The method of any one of embodiments 143 to 152, wherein said amphipathic emulsifier is an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 80, polysorbate 85, and combinations thereof.
  • said amphipathic emulsifier is an amphipathic emulsifier selected from the group consisting of polysorbate 20, polysorbate 80, polysorbate 85, and combinations thereof.
  • Embodiment 156 The method of any one of embodiments 143 to 152, wherein said composition further comprises a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • a co-solvent selected from the group consisting of polyethylene glycol, ethanol, propylene glycol, glycerol, and combinations thereof.
  • Embodiment 157 The method of any one of embodiments 143 to 152, wherein said lipid base comprises coconut oil and said emulsifier comprises polyoxyethylene (20) sorbitan monolaurate (Polysorbate 20/Tween 20).
  • Embodiment 158 The method of any one of embodiments 143 to 152, wherein said curcuminoid concentration is 10 to 20%, said coconut oil concentration is 20 to 30%, and said emulsifier is 50 to 70% polysorbate 20.
  • Embodiment 159 The method of embodiment 158, wherein said BCC further comprises an antioxidant.
  • Embodiment 160 The method of embodiment 159, wherein said antioxidant is vitamin E or butryatedhydroxytoluene (BHT).
  • said antioxidant is vitamin E or butryatedhydroxytoluene (BHT).
  • Embodiment 161 The method of embodiment 160, wherein said antioxidant is vitamin E at a concentration of less than 1 % by weight.
  • Embodiment 162 The method of any one of embodiments 143 to 161, wherein said method of treating PSACH is initiated when said patient in need exhibits a decrease in linear bone growth, when a waddling gait develops, or both.
  • Embodiment 163. The method of any one of embodiments 143 to 162, wherein said method of treating PSACH is initiated after a positive genetic test for mutations in cartilage oligomeric matrix protein (COMP).
  • COMP cartilage oligomeric matrix protein
  • Embodiment 164 The method of any one of embodiments 143 to 163 , wherein said method of treating PSACH provides for an increase in femur length or an increase in stature in said PSACH individual in need thereof.
  • Embodiment 165 The method of embodiment 164, wherein said femur length or stature is improved femur length or stature relative to an untreated PSACH individual.
  • Embodiment 166 The method of embodiment 164, wherein said improvement in stature comprises an increase in height and a reduction in the standard deviation from the normal in the height compared to non-PSACH individuals of the same age.
  • Embodiment 167 The method of embodiment 166, wherein said decrease in the standard deviation is a reduction by 0.5.
  • Embodiment 168 The method of any one of embodiments 166 to 167, wherein said decrease in the standard deviation is reduction by 1.0.
  • Embodiment 169 The method of any one of embodiments 166 to 168, wherein said decrease in the standard deviation is a reduction to less than 2.0 standard deviations from the mean.
  • Embodiment 170 The method of any one of embodiments 166 to 169, wherein the decrease in standard deviation is measured after six months of treatment.
  • Embodiment 171 The method of any one of embodiments 166 to 170, wherein the decrease in standard deviation is measured after six months of treatment and said BCC is provided three times daily.
  • Embodiment 172 The method of any one of embodiments 166 to 171, wherein said improved femur length or stature is observed after the age of eight (8) in PSACH individuals administered BCCs.
  • Embodiment 173 The method of any one of embodiments 143 to 172, wherein said non- PSACH individuals are ethnically matched.
  • Embodiment 174 The method of any one of embodiments 143 to 173, wherein said treating comprises a reduction in joint degeneration.
  • Embodiment 175. The method of any one of embodiments 143 to 174, wherein said reduction in joint degeneration is measured after six months of said providing of said BCC.
  • Embodiment 176 The method of any one of embodiments 143 to 175, wherein said treating comprises a reduction in symptoms of osteoarthritis.
  • Embodiment 177 The method of any one of embodiments 143 to 176, wherein said reduction in symptoms is measured after six months of said providing said BCC.
  • Embodiment 178 The method of any one of embodiments 143 to 177, wherein said BCC is provided twice daily.
  • Embodiment 179 The method of any one of embodiments 143 to 178, wherein said reduction in symptoms is a reduction in the use of pain medication.
  • Embodiment 180 The method of any one of embodiments 143 to 179, wherein said pain medication is an over-the-counter pain medication or a prescription pain medication.
  • Embodiment 181 The method of any one of embodiments 143 to 180, wherein said reduction in symptoms is at least a 10% reduction in pain reporting information on the visual analogue scale (VAS) after at least 30 days of daily administration.
  • VAS visual analogue scale
  • Embodiment 182 The method of any one of embodiments 143 to 181, wherein said reduction in symptoms is at least a 10% reduction in pain on the Wong-Baker scale after at least 30 days of daily administration.
  • Embodiment 183 The method of any one of embodiments 143 to 182, wherein said reduction in symptoms is at least a 10% reduction in pain on the WOMAC scale after at least 30 days of daily administration.
  • Embodiment 184 The method of any one of embodiments 143 to 183, wherein said reduction in symptoms is at least a 10% reduction in pain on the SF-36 scale after at least 30 days of daily administration.
  • Embodiment 185 The method of any one of embodiments 143 to 184, wherein said reduction in symptoms is at least a 10% reduction in pain on the HQRL scale after at least 30 days of daily administration.
  • Embodiment 186 The method of any one of embodiments 143 to 185, wherein said reduction in symptoms is a reduction in pain with walking after at least 30 days of daily administration.
  • Embodiment 187 The method of any one of embodiments 143 to 186, wherein said reduction in pain with walking is a reduction in pain intensity (PI) compared to a baseline PI without treatment with said BCC.
  • PI pain intensity
  • Embodiment 188 The method of any one of embodiments 143 to 187, wherein said reduction in pain with walking is a reduction in the time to moderate pain (TTMP) compared to a baseline measurement without treatment with said BCC.
  • TTMP time to moderate pain
  • Embodiment 189 The method of any one of embodiments 143 to 188, wherein said reduction in symptoms is a reduction in a Knee Injury and Osteoarthritic Score (KOOS).
  • KOOS Knee Injury and Osteoarthritic Score
  • Embodiment 190 The method of any one of embodiments 143 to 189, wherein said reduction in symptoms is an improvement in knee biomechanical markers.
  • Embodiment 191 The method of any one of embodiments 143 to 190, wherein said reduction in symptoms is a reduction in morning stiffness.
  • Embodiment 192 The method of any one of embodiments 143 to 192, wherein said treading comprises reducing inflammation.
  • Bigenic mice are generated by introducing DNA-containing expression cassettes derived from two plasmids, pTRE-MT-COMP (D469del-COMP mutation) and pTET-On-Col II as previously described Posey et al., “An inducible cartilage oligomeric matrix protein mouse model recapitulates human pseudoachondroplasia phenotype.” Am J Pathol, 175:1555-63, (2009). Mice express D469del-COMP protein in all tissues expressing type II collagen, in the presence of doxycycline (DOX 500 ng/ml) administered through drinking water (with 5% wt/vol sucrose) pre- and postnatally.
  • DOX 500 ng/ml doxycycline
  • mice are healthy and reproduced.
  • C57BL/6 mice are used as controls since the wild-type (WT)- COMP mice show no phenotypic differences in our previous studies Posey et al., “An inducible cartilage oligomeric matrix protein mouse model recapitulates human pseudoachondroplasia phenotype.” Am J Pathol, 175: 1555-63, (2009).
  • Mice are housed in single-sex groups after weaning (P21) and fed standard chow (PicoLab rodent diet 20 #5053, LabDiet, St. Louis, MO). The Animal Welfare Committee at the University of Texas Medical School at Houston approved these studies and all experiments complied with the Guide for the Care and Use of Laboratory Animals: Eighth Edition, ISBN- 10: 0-309-15396-
  • DOX 500 ng/ml
  • Curcumin is administered by gavage 5 days per week beginning at P7 until joint collection at P28.
  • the dose is 82.3 mg/kg (human equivalent dose assuming a 60 kg human) for IX and 164.6 mg/kg for 2X doses.
  • the IX dose is selected based on FDA Guidance on Human Equivalent Dose Determination and Stratum Nutrition (Carthage, MO) recommendations based on work with rats Yabas et al., “A Next Generation Formulation of Curcumin Ameliorates Experimentally Induced Osteoarthritis in Rats via Regulation of Inflammatory Mediators.” Front Immunol, 12:609629, (2021). Curcumin was provided by Stratum Nutrition.
  • Mouse limbs are fixed in 95% vol/vol ethanol for immunostaining for human COMP (Abeam Cambridge, MA abll056-rat 1 :100), rabbit polyclonal COMP 1:300 (Kamiya, Seattle, WA), goat polyclonal Type II collagen 1:200 (Santa Cruz Biotechnology, Dallas, Texas), pS6 (1 :200 2215S rabbit polyclonal Cell Signaling Technology), interleukin 16 (IL16) (Santa Cruz Biotechnology; sc- 7902, 1:100), PCNA staining kit (Invitrogen, Frederick, MD 93-1143), IL10 (1:200 bs-0698R Bioss Antibodies Woburn, MA) or in 10% wt/vol formalin for terminal deoxynucleotidyl transferase-mediated deoxy uridine triphosphate-biotin nick end labeling (TUNEL) staining.
  • COMP Abeam Cambridge, MA abll056-rat 1 :100
  • the COMP rat antibody does not cross-react with endogenous mouse COMP and only recognizes human COMP.
  • Species-specific biotinylated secondary antibodies are incubated with each section for 1 hour following streptavidin/HRP incubation and chromogen detection for visualization. At least 8 C57BL/6 and 8 MT-COMP mice are examined for each administration.
  • Limb length measurements Hind limbs are obtained from 10 male mice for each group and the soft tissue is carefully removed. The hind limb is stored in PBS and then subjected to uCT analysis (Sky Scan 1276 from Bruker, International). Measurements are made from end-to-end on femurs using MicroView software (GE Healthcare, Chicago, IL) as previously described Posey et al. , “Skeletal abnormalities in mice lacking extracellular matrix proteins, thrombospondin- 1 , thrombospondin- 3, thrombospondin-5, and type IX collagen.” Am J Pathol, 172: 1664-74. (2008). ANOVA statistic is used to compare the femoral measurements from mice limbs.
  • Example 1 BCC reduces intracellular retention of mutant-COMP in growth plate chondrocytes.
  • mutant human COMP protein is exported to the ECM in the growth plate resting zone (FIGS. 1C, IE) Hecht et al., “CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia” Int J Mol Sci, 24(4):3845 , (2023)..
  • Example 2 BCC treatment decreases markers of inflammation and normalized proliferation and autophagy in the MT-COMP growth plate.
  • FIGS. 2A-T shows that BCC treatment from P7 - P28 represses IL6 inflammation, restores autophagy, and reestablishes chondrocyte proliferation in MT-COMP growth plates compared to the untreated controls.
  • IL6 a proinflammatory cytokine increased by mutant-COMP protein expression Posey et al., “Novel mTORC 1 Mechanism Suggests Therapeutic Targets for COMPopathies.” Am J Pathol, 189:132-146 (2019), Posey el al.
  • Curcumin reportedly reduces OA joint degeneration Wojdasiewicz et al., “The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis.” Mediators Inflamm, 2014:561459, (2014), by stimulating autophagy Li et al., “Curcumin Inhibits Apoptosis of Chondrocytes through Activation ERK1/2 Signaling Pathways Induced Autophagy.” Nutrients, 9:4, (2017), Yao et al.
  • Example 3 Curcumin treatment decreases inflammation, ER stress and increases antiinflammatory activity.
  • FIGS. 3A-0 shows that both TNFa and ILip are elevated in MT-COMP growth plates (FIG. 3B, FIG. 3E) and 2X BCC treatment decreased inflammation (FIG. 3C, FIG. 3F) to control levels (FIG. 3A, FIG. 3D) Hecht et al., “CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia” Int J Mol Sci, 24(4): 3845, (2023). This outcome is consistent with previously reported anti-inflammatory actions of curcumin Wojdasiewicz et al.
  • ER stress fundamental to the mutant-COMP protein pathology, is dramatically reduced by BCC treatment (FIGS. 3G-I), thereby decreasing MIDI levels (FIGS. 3I-L) that dampens a process that blocks autophagy preventing mutant-COMP protein clearance
  • FIGS. 3I-L MIDI levels
  • IL10 an anti-inflammatory protein
  • MMP13 an enzyme that degrades cartilage Wojdasiewicz et al., “The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis.” Mediators Inflamm, 2014:561459, (2014).
  • BCC 2X treatment increases IL10 levels (FIG. 2H) and consistent with its known action, MMP13 levels are reduced (FIGS.
  • Example 4 MT-COMP lost femoral length is rescued by BCC treatment.
  • Example 5 BCC treatment reduces pain in MT-COMP mice.
  • Pain in mice is assessed by proxy assays of changes in instinctive behavior, such as voluntary running and grooming. See Deuis et al., “Methods Used to Evaluate Pain Behaviors in Rodents,” Front Mol Neurosci. 10:284 (2017). Grooming is assessed by scoring the amount of fluorescent dye (15 pl) that remained on the back of the neck after a 4 hr period (same reference). The greater the grooming score the less pain the mice are inferred to have. Controls are consistently around score 4. Mutant-COMP mice consistently and statistically groom less than controls indicating pain.

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Abstract

Le traitement à la curcumine de la pseudoachondroplasie (PSACH), une affection grave sévère, entraîne une diminution de la rétention intracellulaire COMP mutante, une inflammation, une restauration à la fois de l'autophagie et de la prolifération des chondrocytes. Des réductions dans les caractéristiques cliniques sous-jacentes conduisent en outre à une réduction de la douleur, de l'arthrite et à une qualité de vie améliorée. La curcumine est une thérapie efficace lors de perte de croissance des membres associée à la COMPopathie, de dégénérescence articulaire et d'autres états impliquant une inflammation persistante, un stress oxydatif et un bloc d'autophagie.
PCT/US2024/011583 2023-01-17 2024-01-16 Utilisation de compositions contenant de la curcumine biodisponible pour le traitement de pseudoachondroplasie Ceased WO2024155570A2 (fr)

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