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WO2025012697A1 - Procédé de production de biomatériau chargé d'inhibiteur de fabp4 et application pour le traitement de lésions du tendon et du ligament - Google Patents

Procédé de production de biomatériau chargé d'inhibiteur de fabp4 et application pour le traitement de lésions du tendon et du ligament Download PDF

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WO2025012697A1
WO2025012697A1 PCT/IB2024/000326 IB2024000326W WO2025012697A1 WO 2025012697 A1 WO2025012697 A1 WO 2025012697A1 IB 2024000326 W IB2024000326 W IB 2024000326W WO 2025012697 A1 WO2025012697 A1 WO 2025012697A1
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fabp4
composition
tendon
212xc1pct
cuhk
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Po Yee Pauline Lui
Zebin MA
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Chinese University of Hong Kong CUHK
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Chinese University of Hong Kong CUHK
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Priority to AU2024293527A priority Critical patent/AU2024293527A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides

Definitions

  • Rotator cuff tendinopathy affecting the supraspinatus tendon, is a common cause of shoulder pain, with an estimated prevalence of 30% in the general population. 5
  • Lateral elbow tendinopathy is also a highly prevalent tendon disorder, affecting not only tennis players but also the general population. The prevalence of lateral elbow tendinopathy in the general population and manual workers is around 1-3% and 7%, respectively.
  • Non-surgical interventions such as rest, physical therapy, Kinesio taping, shockwave, non-steroid anti-inflammatory drugs (NSAIDs) and corticosteroids have been found to have a low to very low certainty of evidence to support their use.
  • Conservative treatment for patellar tendinopathy is not significantly more effective than minimal intervention or other invasive treatments on improving short-term pain and function.
  • 11 J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 3 CUHK.212XC1PCT Similarly, there is no robust basis for the use of conservative treatments for the management of chronic tendinopathy. 12-15 Surgery is often considered if non-surgical treatments fail.
  • the present invention relates to treating or retarding the progression of tendinopathy as well as promoting surgical repair after tendon rupture by inhibiting the functions of fatty acid- binding protein 4 (FABP4).
  • FBP4 fatty acid- binding protein 4
  • Tendon overuse triggers an inflammatory response that causes a decrease in tenogenic markers and an increase in non-tenogenic markers in tendon-derived stem/progenitor cells (TDSCs), resulting in tissue metaplasia.
  • the present invention discloses the upregulation of FABP4 and its pro-inflammatory and non-tenogenic effects in the clinical samples and animal models of collagenase-induced (CI) inflammatory degenerative tendon injuries.
  • CI collagenase-induced
  • the subject invention can suppress inflammation, inhibit, and/or reverse the erroneous differentiation of TDSCs, and/or enhance the regeneration of degenerative tendons by preserving the pool of TDSCs available for tenogenesis.
  • the subject methods comprise the administration of a FABP4 inhibitor to a subject.
  • the subject methods alleviate CI tendon damages, promote tendon healing by reducing inflammation and oxidative stress, promoting self-renewal and tenogenic activity of TDSCs.
  • a biomaterial is used to administer the FABP4 inhibitor. J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 4 CUHK.212XC1PCT
  • a FABP4 inhibitor such as, for example BMS309403, is loaded into a biomaterial, such as, for example, a GelMA hydrogel.
  • the FABP4 inhibitor or a FABP4 inhibitor-loaded GelMA hydrogel can be used in methods of promoting healing after inflammatory degenerative tendon and ligament injuries and/or tendinopathy.
  • the FABP4 inhibitor is BMS309403, which is a selective and potent biphenyl azole inhibitor of FABP4 (Ki: ⁇ 2nM; IC50: 0.71 ⁇ M).
  • a biological scaffold can be used for the local delivery and slow release of a FABP4 inhibitor to the injured tendon in tendinopathy patients.
  • the loading of a FABP4 inhibitor in GelMA pre-polymers followed by injection of the mixture after UV and/or blue light cross-linking of GelMA pre-polymers can support local administration to the injured tendons and slow release of FABP4 inhibitors, as the GelMA slowly dissolves.
  • FIGs. 1A-1D FIGs. 1A-1D (FIG. 1A) Photomicrographs showing immunohistochemistry (IHC) staining of FABP4 in healthy hamstring tendon samples, healthy patellar tendon samples, and patellar tendinopathy samples.
  • FIGs. 3A-3B Photomicrographs showing IHC staining of FABP4, IL-1 ⁇ , TNF- ⁇ , IL-6, and IL-10 in representative samples of mouse Achilles tendons at at (A) week 2 and week 8 after saline or collagenase injection.
  • FIGs.7A-7C Photomicrographs showing H&E staining and corresponding polarized images of Achilles tendons in WT and FABP4 KO mice at week 2 and week 8 after saline or collagenase injection.
  • FIG. 7B (i) microCT images showing the Achilles tendons of WT and FABP4 KO (Fabp4 -/- ) groups at week 8 after saline or collagenase injection. (ii) Boxplot showing the bone volume (BV) inside tendons in different groups.
  • FIG. 7C Photomicrographs showing IHC staining of IL-1 ⁇ in the Achilles tendons of WT and FABP4 KO mice at week 2 and week 8 after saline or collagenase injection.
  • n 5/group; Scale bar: 50 ⁇ m (insert 200 ⁇ m); black arrow: immunopositive cells.
  • FIG.10A Photographs showing the procedures for (i) mixing LAP, F127 and GelMA pre-polymers with BMS309403, (ii) loading into a syringe and cross-linking with blue light at 405 nm and (iii) injection into the Achilles tendon. The ability of the mixture to eject from the syringe after cross-linking with blue light for different times was shown.
  • FIG. 10B Gross morphology (i, ii) and SEM images (iii-vi) showing surface morphology of GelMA hydrogel without and with loading of BMS309403. Panels (v-vi) are higher magnification of Panels (iii-iv).
  • FIGs. 11A-11D Photomicrographs showing H&E staining and corresponding polarized images of representative samples of WT mouse Achilles tendons at week 2, week 4, and week 8 after single injection of saline, GelMA-only (‘GelMA’) or BMS309403-loaded GelMA hydrogel (‘Gel-BMS’) in the CI tendon injury model.
  • the contralateral uninjured Achilles tendons of the saline group without injury or injection were used as normal controls (‘Normal’).
  • FIG. 11B Photomicrographs showing IHC staining of FABP4 and IL-1 ⁇ of representative samples of WT mouse Achilles tendons at week 2, week 4, and week 8 after single injection of saline, GelMA-only (‘GelMA’) or BMS309403- loaded GelMA hydrogel (‘Gel-BMS’) in the CI tendon injury model.
  • FIG. 11C microCT images showing ectopic mineralized tissue inside the WT mouse Achilles tendons after single injection of saline (‘Saline’), GelMA-only (‘GelMA’) or BMS309403- loaded GelMA hydrogel (‘Gel-BMS’) in the CI tendon injury model at week 8 after treatment.
  • FIG.12B Boxplot showing the CFU of different groups.
  • compositions containing amounts of ingredients where the term “about” is used, these compositions contain the stated amount of the ingredient with a variation (error range) of 0-10% around the value (X ⁇ 10%). In other contexts, the term “about” is used provides a variation (error range) of 0-10% around a given value (X ⁇ 10%).
  • this variation represents a range that is up to 10% above or below a given value, for example, X ⁇ 1%, X ⁇ 2%, X ⁇ 3%, X ⁇ 4%, X ⁇ 5%, X ⁇ 6%, X ⁇ 7%, X ⁇ 8%, X ⁇ 9%, or X ⁇ 10%.
  • ranges are stated in shorthand to avoid having to set out at length and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range.
  • a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc. Values having at least two significant digits within a range are envisioned, for example, a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values. When ranges are used herein, combinations and subcombinations of ranges (e.g., subranges within the disclosed range) and specific embodiments therein are explicitly included.
  • Treatment “Treatment”, “treating”, “palliating” and “ameliorating” (and grammatical variants of these terms), as used herein, are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit. A therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease or symptom thereof or injury such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the injury, disease or symptom thereof.
  • effective amount or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease or injury treatment.
  • the therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and disease condition J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 9 CUHK.212XC1PCT being treated, e.g., the weight and age of the subject, the severity of the disease or injury condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response, e.g., retarding the progression of chronic tendinopathy or promoting healing after inflammatory degenerative tendon tear and surgical repair.
  • the method comprises administration of one or multiple doses of the compositions of the subject invention.
  • the method may comprise administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or more therapeutically effective doses of a composition of the subject invention as described herein.
  • doses may be administered over the course of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 30 days, about 4 weeks, about 6 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 26 weeks, or more than 26 weeks.
  • doses may be administered daily, every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 10 days, once every 14 days, once every 21 days, once every 30 days, once every about 4 weeks, once every about 6 weeks, once every about 8 weeks, once every about 12 weeks, once every about 16 weeks, once every about 20 weeks, once every about 24 weeks, or once every about 26 weeks.
  • treatment of a subject with a therapeutically effective amount of the compositions of the invention can include a single treatment or can include a series of treatments. It will also be appreciated that the effective dosage of a composition used for treatment may increase or decrease over the course of a particular treatment.
  • the term “subject” refers to an animal, needing or desiring delivery of the benefits provided by a therapeutic composition.
  • the animal may be, for example, a mammal, including, humans, pigs, horses, goats, cats, mice, rats, dogs, apes, chimpanzees, orangutans, guinea pigs, hamsters, cows, and sheep.
  • These benefits can include, but are not limited to, the treatment of a health condition, disease or disorder; prevention of a health condition, disease or disorder; enhancement of the function of tendons and/or ligaments, in the body.
  • the subject can be of any age or stage of development, including infant, toddler, J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 10 CUHK.212XC1PCT adolescent, teenager, adult, or senior.
  • the terms “subject” and “patient” can be used interchangeably.
  • scaffold refers to a temporary structure used as a support system to aid in drug delivery to the damaged or diseased areas.
  • reduceds or “retards” is meant a negative alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.
  • increases is meant as a positive alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.
  • compositions according to the subject invention utilize a FABP4 inhibitor, including, for example, BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, and other triazolopyrimidine derivatives (e.g., compounds 1-58, as disclosed in Floresta G, Patamia V, Zagni C, Rescifina A. Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. An update from 2017 to early 2022.
  • a FABP4 inhibitor including, for example, BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, and other triazolopyrimidine derivatives (e.g., compounds 1-58, as disclosed in Floresta G, Patamia V, Zagn
  • RNA interference e.g., 5′-CACCGAGATTTCCTTCAAA-3′ (SEQ ID NO: 2) targeting FABP4 expression, benzbromarone (a uricosuric agent), polyclonal and monoclonal FABP4 neutralizing antibodies, such as, for example, CA33 (see commercially available CA33 at worldwide website: creativebiolabs.net/Anti-FABP4-Recombinant-Antibody-clone-CA33- 22932.htm) and 2E4.
  • shRNA short hairpin
  • RNAi RNA interference
  • CA33 see commercially available CA33 at worldwide website: creativebiolabs.net/Anti-FABP4-Recombinant-Antibody-clone-CA33- 22932.htm
  • the FABP4 inhibitor is BMS309403.
  • J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 11 CUHK.212XC1PCT embodiments to create a short hairpin RNA (shRNA), a nine-nucleotide loop (5′- TTCAAGAGA-3′) was placed to separate the sense and antisense sequences for RNAi.
  • the FABP4 inhibitor can be present in a biomaterial at a concentration of about 0.01 mg/mL to about 1000 mg/mL, about 0.1 mg/mL to about 100 mg/mL, about 1 mg/mL to about 75 mg/mL, or about 50 mg/mL.
  • the FABP4 inhibitor can be administered without the use of a biomaterial to a subject at a dose of about 0.01 mg/kg to about 1000 mg/kg, about 0.1 mg/kg to about 100 mg/kg, about 1 mg/kg to about 75 mg/kg, or about 20 mg/kg.
  • the FABP4 inhibitor can be incorporated into a composite scaffold composed of synthetic and/or natural polymers.
  • the synthetic polymers include, for example, to poly- ⁇ -caprolactone (PCL), poly-L-lactide (PLLA), and poly (lactin-co-glycolic acid) (PLGA).
  • natural polymers include, for example, type I collagen, alginate, chitosan, gelatin and decellularized tendon matrix.
  • Gelatin is a natural hydrophilic polymer produced by hydrolysis and denaturation of collagen under high temperature. Gelatin shows good biocompatibility, solubility and degradability as well as lower antigenicity compared to collagen.
  • the thermostability of gelatin is poor and chemical cross-linking of gelatin may affect its biocompatibility as some cross-linking agents are poisonousness.
  • the polymer is Gelatin methacryloyl (GelMA), which is produced by modifying gelatin with methacrylic anhydride (MA).
  • GelMA Gelatin methacryloyl
  • MA methacrylic anhydride
  • a solution of pre-polymers such as, for example, a GelMA pre-polymer, comprising the FABP4 inhibitor crosslink under UV and/or blue light when a photoinitiator is added, resulting in a hydrogel with good thermostability, biocompatibility and degradation properties.
  • a FABP4 inhibitor can be mixed with a polymer, such as, for example, a GelMA pre-polymer, and a photoinitiator, a thermosensitive poloxamer, or a combination thereof.
  • the photoinitiator is lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) or 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl- 1-propanone (Irgacure-2959), and the thermosensitive poloxamer is poloxamer 407 (e.g., PluronicTM F-127 (BASF, Ludwigshafen, Germany)).
  • the photoinitiator LAP is at a concentration of about 0.001% to about 10%, about 0.01% to about 5%, about 0.01% to about 1%, or about 0.25%.
  • the thermosensitive poloxamer 407 is at a concentration about 0.001% to about 10%, about 0.01% to about 5%, about 0.1% to about 1%, or about 0.1% relative to amount of the photoinitiator in the J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 12 CUHK.212XC1PCT composition.
  • the polymer GelMA pre-polymer is at a concentration of about 0.01% w/v to about 50% w/v, about 0.1% w/v to about 10% w/v, or about 5% w/v.
  • the mixture can be cross-linked by UV or blue light before application of the composition to the subject.
  • the UV light is at a wavelength of about 320 nm to about 390 nm and the blue light is at a wavelength of about 405 nm.
  • the cross-linking of the said mixture can occur for about 1 second to about 1 minute.
  • BMS309403 is mixed with GelMA pre-polymers, LAP (0.25% in PBS (phosphate buffered saline)) and F127 thermosensitive poloxamer (0.1% of LAP) and cross-linked with blue light at 405 mm for about 1 second to about 1 minute or about 14 seconds and applied to the injured tendon and/or ligament.
  • the subject compositions are formulated as an orally-consumable product, such as, for example a food item, capsule, pill, or drinkable liquid.
  • An orally deliverable pharmaceutical is any physiologically active substance delivered via initial absorption in the gastrointestinal tract or into the mucus membranes of the mouth.
  • the topic compositions can also be formulated as a solution that can be administered via, for example, injection, which includes intravenously, intraperitoneally, intramuscularly, subcutaneously or topically.
  • the subject composition can further comprise one or more pharmaceutically acceptable carriers, and/or excipients, and can be formulated into preparations, for example, solid, semi- solid, liquid, forms, such as tablets, capsules, powders, granules, solutions, suppositories, injections, spray, cream, pellets, caplets, troches, lozenges, dispersions, aqueous solution, non- aqueous solution, oil-in-water emulsion, or water-in-oil liquid emulsion.
  • pharmaceutically acceptable as used herein means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.
  • Carriers and/or excipients according the subject invention can include any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers), oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for, e.g., IV use, solubilizers (e.g., Polysorbate 65, Polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione), amino acids (e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavorings, aromatizers, thickeners (e.g.
  • solubilizers e.g.
  • carbomer, gelatin, or sodium alginate coatings, preservatives (e.g., Thimerosal, benzyl alcohol, polyquaterium), antioxidants (e.g., ascorbic acid, sodium J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 13 CUHK.212XC1PCT metabisulfite), tonicity controlling agents, absorption delaying agents, adjuvants, bulking agents (e.g., lactose, mannitol) and the like.
  • preservatives e.g., Thimerosal, benzyl alcohol, polyquaterium
  • antioxidants e.g., ascorbic acid, sodium J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 13 CUHK.212XC1PCT metabisulfite
  • tonicity controlling agents
  • compositions of the subject invention can be formulated for administration via injection, for example, as a solution or suspension.
  • the solution or suspension can comprise suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, phosphate buffered saline (PBS), Dimethylsulfoxide (DMSO), polyethylene glycol, or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, non-irritant, fixed oils, including synthetic mono- or diglycerides.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, phosphate buffered saline (PBS), Dimethylsulfoxide (DMSO), polyethylene glycol, or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, non-irritant, fixed oils, including synthetic mono- or diglycerides
  • a FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial such as, for example, GelMA
  • GelMA can be used for the treatment of tendon and/or ligament injuries, chronic tendinopathy, and for the promotion of healing after inflammatory degenerative tendon and ligament injuries.
  • Tendons and ligaments that may develop tendinopathy due to change of loading such as, for example, overuse in the Achilles tendon, patellar tendon, rotator cuff, extensor Carpi radialis brevis and medial common flexor tendon of the elbow, plantar fascia, and the flexor tendon of finger.
  • the affected tendon and ligament can be presented with pain and swelling without and with tear.
  • a FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial can be applied to the painful and/or injured tendon or ligament by, for example, local injection.
  • a FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial can be applied during or after surgical repair by, for example, injection after surgery or direct application of the FABP4 inhibitor and/or FABP4 inhibitor-loaded biomaterial to the surgically repaired tendon and/or ligament during surgery.
  • FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial can be used for enhancing tissue repair, particularly tendon and/or ligament tissue.
  • the FABP4 inhibitor and/or FABP4 inhibitor-loaded biomaterial can be used to promote tendon or ligament regeneration.
  • the FABP4 inhibitor and/or J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 14 CUHK.212XC1PCT FABP4 inhibitor-loaded biomaterial can be used in forms of putty, scaffolds, or injectable hydrogel.
  • the administration of a FABP4 inhibitor and/or FABP4 inhibitor-loaded biomaterial alleviates tendon damages, reduces ectopic bone formation, reduced walking pain.
  • the administration of a FABP4 inhibitor and/or FABP4 inhibitor-loaded biomaterial reduces the expression of inflammatory cytokines, such as, for example, IL-1 ⁇ , IL-6, and TNF- ⁇ .
  • the administration of a FABP4 inhibitor restores natural tendon healing by promoting the self-renewal ability of TDSCs.
  • the administration of a FABP4 inhibitor enhances anti-inflammatory and anti-oxidative effects of inflammatory TDSCs, as indicated by the reduced expression of inflammatory cytokine (Tnfa) and ER stress markers (Chop, Grp78).
  • the administration of a FABP4 inhibitor redirects the cell fate of inflammatory TDSCs towards tenocyte lineage by promoting the expression of tenogenic markers (Tnmd, Scx) and reducing the expression of osteogenic marker (Runx2) in inflammatory TDSCs.
  • the present invention discloses the method of producing FABP4 inhibitors-loaded biomaterials and the use of FABP4 inhibitors and/or FABP4 inhibitors-loaded biomaterials for treating or retarding the progression of chronic tendinopathy as well as promotion of healing after inflammatory degenerative tendon tear and surgical repair.
  • the present invention provides methods for treating chronic tendinopathy in a patient with a FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial.
  • the symptoms, and pathological changes of tendons in a patient with tendinopathy are reversed after local administration of a FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial.
  • the progression of tendinopathy is retarded after local administration of FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial.
  • the development of tendinopathy is prevented after local administration of FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial.
  • healing after degenerative tendon tear and surgical repair is improved after local administration of FABP4 inhibitor and/or a FABP4 inhibitor-loaded biomaterial.
  • the pathological tendon tissue was excised.
  • the control groups shared similar subject inclusion and exclusion criteria except that they had no history or current clinical signs of tendon injury and tendon pain.
  • Healthy tendons were obtained from the remnant of hamstring tendon autograft or patellar tendon autograft during anterior cruciate ligament reconstruction (ACLR).
  • ACLR anterior cruciate ligament reconstruction
  • the tendon tissues were fixed, dehydrated and paraffinized in tissue blocks for storage.
  • IHC immunohistochemistry
  • 5- ⁇ m-thick sections were cut and mounted on coated slides. After deparaffination, the sections were rehydrated, decalcified, quenched of endogenous peroxidase activity, and treated with 10 mM citrate buffer at 65 o C for 20 min for antigen retrieval.
  • the sections were incubated with specific antibodies against FABP4 (1:200) at 4 o C overnight. The primary antibodies were replaced with blocking solution in the controls. HRP-conjugated goat anti- rabbit secondary antibody (1:500) was used and the immunopositivity was visualized using the DAB substrate kit according to the manufacturer’s protocol. After counterstaining with hematoxylin, the sections were dehydrated with graded ethanol and xylene, mounted with p- xylene-bis-pyridinium bromide (DPX) permount (SigmaAldrich, St Louis, MO) and examined under light microscopy (DM5500; Leica Microsystems Wetzlar GmbH, Wetzlar, Germany).
  • DPX p- xylene-bis-pyridinium bromide
  • a positive signal was shown as brown color. All the incubation times and conditions were strictly controlled. The pathological and healthy tendons were stained in the same batch. Representative images were presented. Image analysis was done using the Image Pro Plus software (MediaCybernetics). The immunopositive signal was measured and presented as integrated optical density (IOD/mm 2 ) of area of interest.
  • EXAMPLE 2 CO-LOCALIZATION OF FABP4 WITH INFLAMMATORY CYTOKINES IN HUMAN ROTATOR CUFF TENDINOPATHY Co-immunofluorescent staining of FABP4 with IL-1 ⁇ and TNF- ⁇ in healthy tendon samples and rotator cuff tendinopathy samples collected as described above was done.
  • the sections were stained with primary antibodies against FABP4 (1:200), washed and stained with primary antibodies against IL-1 ⁇ (1:200) or primary antibodies against TNF- ⁇ (1:200). After washing, the sections were stained with anti-rabbit Alexa Fluor® 488 (1:500) and anti-goat Alexa Fluor® 555 (1:500).
  • the sections were washed and counterstained with 4′-6-diamidino- 2-phenylindole (DAPI) before examination with a fluorescent microscope (FIG.2).
  • DAPI 4′-6-diamidino- 2-phenylindole
  • FIG.2 The results showed that the expression of IL-1 ⁇ and TNF- ⁇ increased in rotator cuff tendinopathy samples and the expression of FABP4 co-localized with the expression of IL-1 ⁇ and TNF- ⁇ , particularly at the blood vessels and tendon cells, supporting interaction of FABP4 and inflammatory cytokines in the pathogenesis of tendinopathy.
  • EXAMPLE 3 UPFGULATION OF FABP4 AND INFLAMMATORY CYTOKINES IN THE MOUSE CI ANIMAL MODEL
  • 20 ⁇ l of 1% bacterial collagenase I (0.1 mg) or saline was injected in the mid-substance of one Achilles tendon of each mouse.
  • the Achilles tendon was harvested for IHC staining of FABP4, pro- inflammatory cytokines (IL-1 ⁇ , IL-6, TNF- ⁇ ) and anti-inflammatory cytokine (IL-10).
  • the IHC staining protocol was similar to the one described in Example 1.
  • the tendon samples were collected at week 2 and week 8 for histology with haemtoxylin and eosin (H&E) staining and IHC staining of pro-inflammatory cytokines (IL-1- ⁇ , TNF- ⁇ , IL-6) and anti-inflammatory cytokine (IL-10).
  • H&E haemtoxylin and eosin
  • Ectopic bone formation in tendon was also examined at week 8 after injection by microCT imaging.
  • the Achilles tendons were harvested and prepared for histology.
  • the tendon samples were stained with H&E after sectioning, deparaffinization, and rehydration.
  • the H&E-stained slides were dehydrated, mounted, and visualized under light and polarization microscopy (DM5500; Leica Microsystems Wetzlar GmbH, Wetzlar,
  • Ectopic bone formation in tendons was examined using a cone-beam microCT system (Bruker Skyscan 1276 in vivo microCT system).
  • the Achilles tendons were scanned with the calf muscle and the calcaneus bone as the landmarks.
  • the images were then 3D-reconstructed after thresholding, using the built-in software.
  • the Achilles tendon-only region was selected as the region of interest (ROI).
  • the bone volume (BV) of ectopic mineralization inside the Achilles tendon was measured.
  • the IHC staining protocol was similar to the one described in Example 1 (FIG.4).
  • EXAMPLE 5—FABP4 INCREASED THE MRNA EXPRESSION OF INFLAMMATORY CYTOKINES Human and mice TDSCs were treated with FABP4 (120 ng/mL) with serum starvation for 24 h. The mRNA expressions of inflammatory cytokines were examined by quantitative real-time-polymerase chain reaction (qRT-PCR) (FIG.5).
  • Mouse TDSCs were treated with or without IL-1 ⁇ (10 ng/mL) under serum starvation (2% FBS for immunofluorescent staining and 1% FBS for qRT-PCR) for 48 h.
  • the cells were stained with anti-primary antibodies against FABP4 (1:200) and anti-rabbit Alexa Fluor® 555 (1:500). Afterwards, the cells were washed and counterstained with DAPI before examination with a fluorescent microscope.
  • the expression of Fabp4 in mouse TDSCs with or without IL-1 ⁇ treatment was also examined by qRT-PCR (FIG.6). There was higher expression of FABP4 in human rotator cuff tendinopathy TDSCs compared to healthy hamstring tendon TDSCs.
  • the Achilles tendons were harvested and prepared for H&E histology, microCT imaging of ectopic bone, and IHC staining of pro-inflammatory cytokine (IL-1 ⁇ ).
  • the protocols for histology, microCT imaging and IHC staining were similar to the ones described in Example 1 and Example 4 (FIG.7).
  • Genetic deletion of FABP4 protected tendon from collagenase-induced tendon injury as indicated by lower infiltration of inflammatory cells, lower cellularity, lower vascularity, higher collagen birefringence, absence of chondrocyte-like cells, lower ectopic bone and lower expression of IL-1 ⁇ compared to the injured WT tendons.
  • EXAMPLE 8 PHARMACOLOGICAL INHIBITION OF FABP4 WITH REPEATED INJECTIONS OF BMS309403 PROMOTED TENDON HEALING IN THE CI ANIMAL MODEL J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 19 CUHK.212XC1PCT CI tendon injury was induced by injecting collagenase into the mid-substances of mouse Achilles tendon. At week 1 after CI injury, the animals were randomized into two groups. Vehicles or BMS309403 (20 mg/kg) was injected in the Achilles tendon every 3 days for 4 times in the control and treatment groups, respectively.
  • EXAMPLE 9 PHARMACOLOGICAL INHIBITION OF FABP4 WITH REPEATED INJECTIONS OF BMS309403 PROMOTED TENDON HEALING PARTIALLY VIA SUPPRESSION OF INFLAMMATION IN THE CI ANIMAL MODEL.
  • the CI tendon injury model and BMS309403 treatment were the same as that described in Example 8.
  • the tendon samples were subjected to IHC staining of inflammatory cytokines IL-1 ⁇ , IL-6, and TNF- ⁇ .
  • the IHC staining protocol was similar to the one described in Example 1.
  • BMS309403 promoted tendon healing after CI tendon injury partly via suppression of inflammatory cytokines.
  • EXAMPLE 10 OPTIMIZATION OF PROTOCOL FOR THE PREPARATION OF BMS309403-LOADED GELMA HYDROGEL COMPLEX FOR LOCAL DELIVERY TO THE ACHILLES TENDON
  • Photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) (0.25% in PBS) at 200 ⁇ L was mixed with 0.2 mg F127 thermosensitive poloxamer (final 0.1% of LAP) and 10 mg GelMA pre-polymers (final 5% w/v). The mixture was filtered and 200 ⁇ L of the mixture was then mixed without or with 10 mg BMS309403.
  • the injured tendons were injected either with saline, GelMA-only, or BMS309403-loaded GelMA hydrogel once.
  • the Achilles tendons were harvested for histology, IHC staining, and microCT imaging.
  • the contralateral uninjured Achilles tendons of the saline group without injury or injection were used as normal controls.
  • the animals were also subjected to gait analysis at week 2 and week 8 after treatment, before sacrifice. Healthy, uninjured animals were used as controls for the gait analysis. Histology was done as described in Example 4.
  • the IHC staining protocol was similar to the one described in Example 1.
  • Stand time s
  • swing time s
  • CUHK.212XC1PCT mean foot loading intensity, print area (cm 2 ) and swing speed (cm/s) were calculated from the middle stride using the built-in motion analysis software.
  • the gait parameters of the injured/treated limb were normalized by the values of the contralateral uninjured limb of each animal.
  • CI tendon injury reduced the normalized stand time, print area and swing speed as well as increased the normalized swing time in the injured limb at week 2 and week 8 after treatment in the Saline group compared to the Control group. There was no significant change in the normalized mean foot loading intensity in the Saline group compared to the Control group. Similar results were observed in the GelMA group. Treatment of injured tendons with BMS309403-loaded GelMA hydrogel reversed the gait parameters and there were no significant difference in the gait parameters in the BMS309403-loaded GelMA group compared to the Control group at week 2 and week 8 after treatment.
  • BMS309403-loaded GelMA Single injection of BMS309403-loaded GelMA at a lower cumulative dose, therefore, promoted tendon healing in the CI tendon injury model with improvement in tendon histology, ectopic bone formation, and walking pain, and reduced expression of inflammatory cytokine.
  • BMS309403-loaded GelMA therefore can be used as a novel treatment of inflammatory degenerative tendon and ligament injuries as well as tendinopathy.
  • TDSCs TENDON-DERIVED STEM/PROGENITOR CELLS
  • EXAMPLE 13 FBP4 INCREASED ER STRESS, ENHANCED OSTEOGENESIS AND REDUCED TENOGENESIS OF INFLAMMATORY TDSCS
  • Mouse TDSCs were seeded in 12-well culture plates overnight and treated with FABP4 (120 ng/mL) in the presence of IL-1 ⁇ (10 ng/mL) in 1% FBS for 48 h.
  • the mRNA expression of ER stress marker (Chop), osteogenic marker (Bglap) and tenogenic marker (Col1a1) were assessed by qRT-PCR (FIG.13). The results showed that there were significantly higher expressions of Chop and Bglap, but lower expression of Col1a1 after treatment of inflammatory TDSCs with FABP4.
  • EXAMPLE 14 BMS309403 REDUCED INFLAMMATION, ER STRESS, OSTEOGENESIS AND PROMOTED TENOGENESIS OF INFLAMMATORY TDSCS
  • Mouse TDSCs were seeded in 12-well culture plates overnight and treated with BMS309403 (10 ⁇ M) in the presence of IL-1 ⁇ (10 ng/mL) at 1% FBS for 48 h.
  • the mRNA expressions of pro-inflammatory marker (Tnfa), ER stress marker (Chop, Grp78), tenogenic makers (Tnmd, Scx) and osteogenic marker (Runx2) were assessed by qRT-PCR (FIG.14).
  • a method of treating an injury to a tendon or ligament in a subject comprising administering to the subject a composition comprising an effective dose of a fatty acid-binding protein 4 (FABP4) inhibitor.
  • FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, a triazolopyrimidine derivative, a short hairpin RNA (shRNA) that targets FABP4 expression, RNA interference (RNAi) that targets FABP4 expression, benzbromarone, a polyclonal FABP4 neutralizing antibody, a monoclonal FABP4 neutralizing antibody, or any combination thereof.
  • shRNA short hairpin RNA
  • RNAi RNA interference
  • Embodiment 3 The method of embodiment 1 or 2, wherein the FABP4 inhibitor is BMS309403.
  • Embodiment 4. The method of any preceding embodiment, wherein the monoclonal neutralizing antibody is CA33 or 2E4.
  • Embodiment 5. The method of any preceding embodiment, wherein the composition further comprises a polymer.
  • Embodiment 6. The method of embodiment 5, wherein the polymer is gelatin methacryloyl (GelMA), poly- ⁇ -caprolactone (PCL), poly-L-lactide (PLLA), poly (lactin-co- glycolic acid) (PLGA), type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.
  • Embodiment 7. Embodiment 7.
  • the composition further comprises a photoinitiator and a thermosensitive poloxamer.
  • Embodiment 8 The method of embodiment 7, wherein the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) and the thermosensitive poloxamer is poloxamer 407. J: ⁇ CUHK ⁇ 212XC1PCT ⁇ Application ⁇ CUHK-212XC1PCT-Application.docx/brb 24 CUHK.212XC1PCT Embodiment 9.
  • the cross-linking comprises applying ultraviolet or blue light to the composition for about 1 second to about 1 minute.
  • Embodiment 11 The method of any preceding embodiment, wherein the administration of the composition comprises injecting the composition into the subject or direct application of the composition to the injured tendon and/or ligament.
  • Embodiment 12. The method of any preceding embodiment, wherein the administering to the subject comprises injecting the composition into the subject or oral administration of the composition to the subject.
  • Embodiment 13 The method of any preceding embodiment, wherein the FABP4 inhibitor is at a concentration of about 50 mg/mL in the composition.
  • Embodiment 14 A composition comprising a fatty acid-binding protein 4 (FABP4) inhibitor, and a polymer.
  • composition of embodiment 14, wherein the FABP4 inhibitor is BMS309403, HM50316, HTS01037, cobimetinib, darifenacin, fosaprepitant, paliperidone, risperidone, pimozide, a triazolopyrimidine derivative, a short hairpin RNA (shRNA) that targets FABP4 expression, RNA interference (RNAi) that targets FABP4 expression, benzbromarone, a polyclonal FABP4 neutralizing antibody, a monoclonal FABP4 neutralizing antibody, or any combination thereof.
  • Embodiment 16 The composition of embodiment 14 or 15, wherein the FABP4 inhibitor is BMS309403.
  • Embodiment 17 The composition of any of embodiments 14-16, wherein the monoclonal neutralizing antibody is CA33 or 2E4.
  • Embodiment 18 The composition of any of embodiments 14-17, wherein the polymer is GelMA, PCL, PLLA, PLGA, type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.
  • Embodiment 19 The composition of any of embodiments 14-18, wherein the composition further comprises a photoinitiator and a thermosensitive poloxamer.
  • Embodiment 20 The composition of any of embodiments 14-16, wherein the monoclonal neutralizing antibody is CA33 or 2E4.
  • Embodiment 18 The composition of any of embodiments 14-17, wherein the polymer is GelMA, PCL, PLLA, PLGA, type I collagen, alginate, chitosan, gelatin, decellularized tendon matrix, or any combination thereof.
  • composition of embodiment 19, wherein the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).
  • Embodiment 21 The composition of embodiment 19 or 20, wherein the thermosensitive poloxamer is poloxamer 407.
  • Embodiment 22 The composition of any of embodiments 14-21, wherein the FABP4 inhibitor is at a concentration of about 50 mg/mL.
  • Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17(11): 1498-503. 40. Cataltepe O, Arikan MC, Ghelfi E, Karaaslan C, Ozsurekci Y, Dresser K, et al. Fatty acid binding protein 4 is expressed in distinct endothelial and non-endothelial cell populations in glioblastoma. Neuropathol Appl Neurobiol 2012; 38(5): 400-10. 41. Fuseya T, Furuhashi M, Matsumoto M, Watanabe Y, Hoshina K, Mita T, et al.
  • FABP4 alleviates endoplasmic reticulum stress-mediated ischemia-reperfusion injury in PC12 cells via regulation of PPAR ⁇ .
  • Knocking out or pharmaceutical inhibition of fatty acid binding protein 4 (FABP4) alleviates osteoarthritis induced by high-fat diet in mice.
  • Look C Morano I, Ehrhart-Bornstein M, Bornstein SR, Lamounier-Zepter V. BMS309403 directly suppresses cardiac contractile function.
  • FABP4 inhibitor attenuates inflammation and endoplasmic reticulum stress of islet in leptin receptor knockout rats.
  • Downregulation of fatty acid binding protein 4 alleviates lipid peroxidation and oxidative stress in diabetic retinopathy by regulating peroxisome proliferator-activated receptor ⁇ -mediated ferroptosis. Bioengineered 2022; 13(4):10540-51.
  • Shi M Guo F, Liao D, Huang R, Feng Y, Zeng X, et al.
  • RNAi-mediated germline knockdown of FABP4 increases body weight but does not improve the deranged nutrient metabolism of diet-induced obese mice.
  • Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab 2013; 17(5): 768-78. 60.
  • the mAb against adipocyte fatty acid-binding protein 2E4 attenuates the inflammation in the mouse model of high-fat diet-induced obesity via toll-like receptor 4 pathway.

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Abstract

La présente invention concerne des procédés destinés à à inhiber FABP4, traiter et retarder la progression de lésions tendineuses dégénératives de la tendinopathie chronique, ainsi que promouvoir la réparation chirurgicale après rupture du tendon et du ligament chez un sujet. La présente invention concerne en outre des procédés de production d'un biomatériau chargé d'inhibiteur de FABP4 et d'application d'un inhibiteur de FABP4 et/ou d'un biomatériau chargé d'inhibiteur de FABP4 dans le traitement d'une lésion du tendon et du ligament chez un sujet.
PCT/IB2024/000326 2023-07-07 2024-06-28 Procédé de production de biomatériau chargé d'inhibiteur de fabp4 et application pour le traitement de lésions du tendon et du ligament Pending WO2025012697A1 (fr)

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Citations (4)

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WO2016009000A1 (fr) * 2014-07-16 2016-01-21 Ethris Gmbh Arn destiné à être utilisé dans le traitement de lésions ligamentaires ou tendineuses
US20170335283A1 (en) * 2014-11-07 2017-11-23 The Trustees Of Columbia University In The City Of New York Osteochondroreticular Stem Cells for Bone and Cartilage Regeneration
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US20120289570A1 (en) * 2011-03-17 2012-11-15 Ernst Lengyel Compositions and methods for treating and/or preventing cancer by inhibiting fatty acid binding proteins
WO2016009000A1 (fr) * 2014-07-16 2016-01-21 Ethris Gmbh Arn destiné à être utilisé dans le traitement de lésions ligamentaires ou tendineuses
US20170335283A1 (en) * 2014-11-07 2017-11-23 The Trustees Of Columbia University In The City Of New York Osteochondroreticular Stem Cells for Bone and Cartilage Regeneration
WO2018192469A1 (fr) * 2017-04-18 2018-10-25 The University Of Hong Kong Inhibiteurs de fabp4 et méthodes de traitement de l'arthrite

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