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WO2025155149A1 - Composition pharmaceutique pour le traitement d'une lésion nerveuse comprenant des exosomes de lait en tant que principe actif - Google Patents

Composition pharmaceutique pour le traitement d'une lésion nerveuse comprenant des exosomes de lait en tant que principe actif

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Publication number
WO2025155149A1
WO2025155149A1 PCT/KR2025/001095 KR2025001095W WO2025155149A1 WO 2025155149 A1 WO2025155149 A1 WO 2025155149A1 KR 2025001095 W KR2025001095 W KR 2025001095W WO 2025155149 A1 WO2025155149 A1 WO 2025155149A1
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WIPO (PCT)
Prior art keywords
milk
nerve
group
exosomes
damage
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PCT/KR2025/001095
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English (en)
Korean (ko)
Inventor
장예지
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Exogenique Co Ltd
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Exogenique Co Ltd
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Publication of WO2025155149A1 publication Critical patent/WO2025155149A1/fr
Pending legal-status Critical Current
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies

Definitions

  • the present invention relates to a novel use of milk exosomes, and more specifically, to a pharmaceutical composition for treating nerve damage comprising milk exosomes as an active ingredient.
  • Exosomes small membrane-enclosed vesicles derived from endosomes, have attracted considerable attention over the past decade. Their importance has been increasingly recognized since their initial discovery in the late 1980s. These naturally occurring extracellular nanovesicles contain biologically active substances such as proteins, microRNA, mRNA, DNA, and other molecules, all of which are essential for facilitating communication between different cell types. Exosomes can be effectively isolated from various types of milk sources, including cow, porcine, yak, camel, human, and goat. Isolated exosomes retain their size and biological activity even when stored at -80°C due to their protective phospholipid bilayer. This layer effectively protects the microRNAs within the exosomes from degradation in the gastrointestinal tract and restricts their further absorption into the intestine.
  • Korean Patent Publication No. 2021-0025568 discloses a composition for preventing, treating, or improving systemic sclerosis containing adipose stem cell-derived exosome as an active ingredient
  • Korean Patent Publication No. 2022-0073565 discloses a composition for treating neurological diseases containing natural product extract pre-treated stem cell-derived exosome and its use.
  • nerve damage containing milk-derived exosome as an active ingredient.
  • the present invention is intended to solve various problems including the above-mentioned problems, and aims to provide a pharmaceutical composition for treating nerve damage containing milk exosomes as an active ingredient, which can rapidly treat nerve damage caused by various trauma due to excellent nerve regeneration promotion effect and no side effects.
  • these tasks are exemplary and the scope of the present invention is not limited thereby.
  • a pharmaceutical composition for treating nerve damage comprising exosomes isolated from milk or goat milk as an active ingredient.
  • Figure 3 shows the in vivo surgical procedure using a rat.
  • A is a photograph showing the preparation before surgery. The surgical site on the left hind leg was shaved and sterilized with 75% ethanol.
  • B is a photograph confirming the exposure of the sciatic nerve. An incision was made along the femoral axis, and the thigh muscle was incised to expose the sciatic nerve. A 20 mm portion of the nerve was marked and resected.
  • C is a photograph showing the reconstruction of the nerve. The nerve defect was treated using autologous grafting (group I), acellular nerve grafting with an exosome-fibrin patch (group II), or acellular nerve grafting with only a fibrin patch (group III).
  • FIG. 4b is a graph showing the size distribution and protein marker analysis results of milk-derived exosomes (M-EVs).
  • M-EVs milk-derived exosomes
  • the size distribution of M-EVs and the results of Western blot analysis of TSG101, MFG-E8, CD63, and CD9 are shown.
  • the size distribution of milk-derived exosomes (M-EVs) was analyzed by dynamic light scattering (DLS), and M-EVs showed a size distribution of approximately 100–150 nm, which is consistent with the typical size range of exosomes.
  • Western blot analysis confirmed the presence of TSG101, CD63, CD9, which are representative exosome marker proteins, and MFG-E8, a major protein of milk-derived exosomes, in M-EVs.
  • Figure 4c is a graph showing the results of evaluating cell proliferation using a CCK-8 assay 24 hours after M-EV treatment in NIH-3T3 cells and SVEC4-10 cells.
  • Figure 4d is a representative image of the wound scratch migration assay in NIH-3T3 cells (0.8 mg/mL).
  • Figure 4e is a graph showing the results of quantitative analysis of M-EVs in the wound closure area.
  • Figure 4f is a representative image of the tube formation assay in SVEC4-10 cells after treatment with 0.4 mg/mL M-EV for 6 h.
  • Figure 4g is a graph showing the results of analyzing the quantification of the number of branch points and tube length 6 hours after M-EV treatment. All data are expressed as mean ⁇ SEM ( * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001, **** p ⁇ 0.0001).
  • Figure 5b is a graph showing the results of quantitative analysis of the ankle angle in the final stance between groups at 8 and 16 weeks after rat surgery for video gait analysis.
  • Group I autologous transplantation
  • Group III acellular nerve graft with fibrin patch alone
  • Group II acellular nerve graft with exosome-fibrin patch
  • Group III acellular nerve graft with exosome-fibrin patch
  • Figure 6a is a representative image of the tibialis anterior (TA) muscle harvested from the affected side (left) and the normal side (right) 16 weeks after surgery.
  • the size and mass of the TA muscle on the affected side were relatively larger in both the autologous transplantation group (group I) and the acellular nerve graft group with exosome-fibrin patch application (group II) compared to the acellular nerve graft group with fibrin patch application alone (group III).
  • group III showed a noticeably smaller muscle size compared to groups I and II.
  • Figure 6b is a graph showing the quantitative analysis of TA muscle recovery expressed as a percentage of the contralateral side at 16 weeks after surgery, based on the analysis of the adductor tibialis muscle weight in rats.
  • Group I autologous transplantation
  • Group II acellular nerve graft group with exosome-fibrin patch applied, 66.22% ⁇ 17.66%)
  • Group III acellular nerve graft group with fibrin patch applied alone, 39.86% ⁇ 14.45%).
  • Figure 7a is a representative image of the hind limb of a rat 16 weeks after surgery, analyzing the ankle contracture angle of the rat.
  • the affected side (left) and the normal side (right) of each experimental group are shown.
  • Groups I (autologous transplantation) and II (acellular nerve graft group with exosome-fibrin patch applied) showed relatively symmetrical limb postures between the affected and normal sides, while Group III (acellular nerve graft group with fibrin patch applied alone) showed a striking difference between the affected and normal sides, reflecting a higher degree of ankle contracture in Group III.
  • Figure 8 is a graph showing representative CMAP (Compound Muscle Action Potential) waveforms and quantitative results at 16 weeks after rat surgery by electrophysiological evaluation.
  • Group I autologous transplantation
  • Group II acellular nerve graft group with exosome-fibrin patch applied
  • Group III acellular nerve graft group with fibrin patch applied alone.
  • P 0.003
  • Figure 9a is a representative toluidine blue-stained cross-sectional image of the regenerated sciatic nerve at 16 weeks post-surgery in rats.
  • the images represent the proximal (upper row) and distal (lower row) parts of each experimental group: autologous graft (group I), acellular nerve graft group with exosome-fibrin patch application (group II), and acellular nerve graft group with fibrin patch application alone (group III). All images were captured at 100x magnification, and the scale bar represents 400 ⁇ m.
  • Figure 9b shows cross-sectional images of toluidine blue staining at 400x magnification.
  • the scale bar represents 100 ⁇ m: autologous transplantation (group I), acellular nerve graft group with exosome-fibrin patch applied (group II), and acellular nerve graft group with fibrin patch applied alone (group III).
  • Figure 9c is a graph showing the results of quantitative analysis of the total number of axons in the proximal and distal parts of the regenerated sciatic nerve at 16 weeks after surgery in rats.
  • Figure 10a is a representative NF200 immunohistochemical staining analysis showing cross-sections of the proximal and distal nerve segments in rats 16 weeks after surgery.
  • the images show the distribution and intensity of NF200 staining across the three groups: autologous grafting (group I), acellular nerve grafting group with exosome-fibrin patch application (group II), and acellular nerve grafting group with fibrin patch application alone (group III).
  • Scale bar 400 ⁇ m.
  • Figure 10b is a graph showing the results of quantitative analysis of NF200 signal intensity in the proximal and distal segments.
  • the average pixel intensity (mean ⁇ SD) was highest in Group I, followed by Group II, and lowest in Group III in both segments.
  • Statistical analysis results showed that Groups I and II had significantly higher intensities than Group III (* P ⁇ 0.05). Error bars represent 95% confidence intervals.
  • Figure 11a is a representative image showing S100 ⁇ expression in the proximal and distal nerve parts of Group I (autologous transplantation), Group II (acellular nerve graft group with exosome-fibrin patch application), and Group III (acellular nerve graft group with fibrin patch application alone) at 16 weeks after rat surgery, according to immunohistochemical staining S100 ⁇ analysis. The images were taken at 100x magnification, and the scale bar represents 400 ⁇ m. Higher S100 ⁇ signal intensities were observed in Group I and Group II compared to Group III, indicating enhanced nerve regeneration.
  • Figure 11b is a graph showing the results of quantitative analysis of the average pixel intensity of S100 ⁇ immunolabeling in the proximal and distal sections.
  • groups I and II showed significantly higher average pixel intensities than group III ( P ⁇ 0.05).
  • groups I and II showed significantly higher intensities than group III ( P ⁇ 0.05).
  • Data are expressed as mean ⁇ standard deviation, and error bars represent 95% confidence intervals.
  • exosome refers to a nano-sized cell-derived vesicle that may be present in all biological fluids, including blood, urine, and culture media of cell cultures. Exosomes are known to be between 30 and 100 nm in size, and are secreted from cells when multivesicular bodies fuse with the cell membrane or are secreted directly through the cell membrane. Exosomes are known to play an important role in various processes such as coagulation, intercellular signaling, and management of metabolic waste.
  • milk exosome refers to exosomes derived from mammalian milk, such as commercial milk or colostrum.
  • colonstrum exosome refers to exosomes derived from milk secreted by mothers immediately after giving birth to their young.
  • milk used in this document refers to cow's milk, but milk from other mammals such as horses, sheep, goats, and camels can also be considered functional equivalents.
  • cow's milk is the most desirable, and "goat milk” produced and distributed from goats can also be an excellent substitute.
  • goat milk is similar in composition to breast milk, making it easy to digest and highly nutritious, and is recognized as a high-quality milk.
  • Horse milk is also used as a milk substitute by nomadic peoples in Central Asia, although it is not common.
  • colostrum milk secreted from the end of pregnancy to several days after delivery.
  • colostrum contains more nutrients and antibodies necessary for survival and growth, and is also preferred in terms of health promotion and nutritional supply because it contains higher levels of antioxidants such as lactoferrin and hemopexin than regular milk.
  • peripheral nerve damage refers to damage to peripheral nerves caused by physical pressure or shock, rather than damage caused by disease.
  • a pharmaceutical composition for treating nerve damage comprising exosomes isolated from milk or goat milk as an active ingredient.
  • the milk or goat milk may be raw milk, commercial milk or goat milk or colostrum.
  • the nerve damage may be damage to a peripheral nerve
  • the peripheral nerve damage may be damage to a trauma, damage to a motor nerve, or damage to a sensory nerve
  • the trauma may be selected from the group consisting of burns, contusions, lacerations, puncture wounds, cuts, abrasions, bedsores, and wounds.
  • the exosome can promote the regeneration of the nerve cell itself or enhance the proliferation or function of Schwann cells surrounding the axons of the nerve cells. It has been confirmed that the exosome can contribute to the recovery of nerve damage through the increase in the axon count of the nerve cell. However, it is possible that the mechanism of this effect is the promotion of nerve cell regeneration or the proliferation and enhancement of the function of Schwann cells surrounding the axons of the nerve cells.
  • the exosome may have a size of 50 to 250 nm.
  • exosomes isolated from milk or goat milk used for treating nerve damage are provided.
  • the present inventors modified a previously reported method for isolating exosomes from milk (Yamauchi et al., Drug Dev. Ind. Pharm. 45(3): 359-364, 2019) to devise a new exosome isolation method (Patent No. 10-2523065).
  • the size distribution of EVs was measured using dynamic light scattering (DLS) (Zetasizer Nano; Malvern Instruments, UK). EV samples were diluted in PBS and analyzed at a backscattering angle of 173° in disposable cuvettes (Rooll Labware, Italy). Data were processed using the software provided with the instrument, and the size distribution of the particles was expressed as a percentage of the number of particles in the sample.
  • DLS dynamic light scattering
  • Example 1 The exosomes isolated in Example 1 were photographed using a transmission electron microscope (Tecnal F20 TEM, FEI Company, USA).
  • EV protein samples were prepared by lysing EVs in RIPA buffer (Thermo Fisher Scientific, USA) containing a cocktail of protease and phosphatase inhibitors (Cell Signaling Technology, USA) to prevent protein degradation.
  • the protein concentration in the lysate was quantified using the bicinchoninic acid (BCA) assay, a colorimetric method for measuring protein concentration.
  • BCA bicinchoninic acid
  • the proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to properly separate the proteins according to their molecular weight.
  • the proteins were then transferred to nitrocellulose membranes (Bio-Rad, USA) using the Turbo transfer system, a fast and efficient membrane transfer method. After transfer, the membranes were blocked in 5% skim milk prepared in TBS-T (Tris-buffered saline containing 0.1% Tween 20) for 1 h at room temperature. Blocking was performed to minimize nonspecific binding of antibodies. The membranes were then incubated overnight at 4°C with primary antibodies targeting EV-specific markers.
  • TBS-T Tris-buffered saline containing 0.1% Tween 20
  • TSG101 (Abcam, UK, ab83, dilution 1:1000), a well-known EV marker associated with the ESCRT pathway
  • CD63 Invitrogen, USA, MA1-19301, dilution 1:2000
  • CD9 Invitrogen, USA, MA1-19301, dilution 1:2000
  • MFG-E8 R&D Systems, USA, AF2805, dilution 1:1000
  • a marker frequently associated with milk-derived EVs a marker frequently associated with milk-derived EVs.
  • HRP horseradish peroxidase
  • NIH-3T3 mouse fibroblast cell line; ATCC, USA
  • SVEC4-10 mouse endothelial cell line; ATCC, USA
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • Gibco, USA antibiotic-antimycotic solution
  • milk-derived extracellular vesicles (Milk-EVs)
  • NIH-3T3 fibroblasts and SVEC4-10 endothelial cells were seeded at a density of 6 ⁇ 103 cells per well in 96-well plates and allowed to attach in complete medium for 12 h. After incubation, the medium was removed, and the cells were washed with Dulbecco's phosphate-buffered saline (DPBS).
  • DPBS Dulbecco's phosphate-buffered saline
  • the cells were then treated with various concentrations of Milk-EVs (0, 0.1, 0.4, 0.8, and 1.2 mg/mL) in serum-free medium for 24 h. After 24 h of treatment, 20 ⁇ L of CCK-8 solution (10% of the total medium volume) was added to each well, and the plates were incubated at 37°C for an additional 2 h. Absorbance was measured at 450 nm using a SpectraMax 34 microplate reader (Molecular Devices, Sunnyvale, CA, USA). Cell proliferation rates were calculated and expressed as a percentage of untreated controls. All experiments were performed in triplicate and results are expressed as mean ⁇ SEM.
  • NIH-3T3 fibroblasts were seeded at a density of 2 ⁇ 10 5 cells per well in 6-well plates and cultured overnight at 37 °C in a 5% CO2 incubator to form a confluent monolayer. After monolayer formation, a straight scratch was created using a sterile scratcher (SPLScar; SPL Life Sciences, Korea), and the cells were carefully washed with phosphate-buffered saline (PBS) to remove debris.
  • SPLScar sterile scratcher
  • PBS phosphate-buffered saline
  • M-EVs were added to the wells at a concentration of 100 ⁇ g/mL (5 ⁇ 10 7 particles/mL) in serum-free medium, and the cells were cultured for 24 h. Images of the wound area were captured using a CK40 culture microscope (Olympus, Japan) at 0 and 24 h. The degree of wound closure was quantified by measuring the closed wound area using ImageJ software (NIH).
  • M-EVs The angiogenic effect of M-EVs was evaluated using a tube formation assay using SVEC4-10 endothelial cells.
  • Matrigel 50 ⁇ L; Corning Matrigel Matrix, Corning, USA
  • SVEC4-10 cells were seeded on the solidified Matrigel at a density of 2 ⁇ 104 cells per well and treated with M-EVs at a concentration of 100 ⁇ g/mL (5 ⁇ 10 7 particles/mL) in serum-free medium.
  • images of tube-like structures were captured using a CK40 culture microscope (Olympus, Japan). Tube formation was analyzed by quantifying the total tube length and the number of branch points using ImageJ software (NIH).
  • DAB diaminobenzidine
  • DLS dynamic light scattering
  • Western blot analysis was performed to detect specific marker proteins, including TSG101, CD63, and CD9, which are associated with the biosynthesis of luminal vesicles and EVs.
  • Western blot is a method to confirm the presence or absence of a specific protein and the expression level in a protein sample, and detects the target protein through an antigen-antibody reaction. These proteins are widely used as markers of exosomes and play an important role in confirming the existence of exosomes.
  • milk fat globular EGF factor 8 (MFG-E8), a major protein of milk-derived exosomes, was also clearly identified.
  • MFG-E8 is a protein abundantly present in milk-derived exosomes and is closely related to the function of exosomes. The above results clearly demonstrate the effective isolation and characterization of exosomes.
  • M-EVs milk-derived extracellular vesicles
  • a series of in vitro assays focusing on cell proliferation, migration, and angiogenesis were performed.
  • the effects of milk-derived extracellular vesicles (M-EVs) on cellular functions were evaluated through a series of in vitro experiments.
  • the proliferation of NIH-3T3 fibroblasts and SVEC4-10 endothelial cells was assessed using the Cell Counting Kit-8 (CCK-8) assay.
  • CCK-8 Cell Counting Kit-8
  • Group I had the shortest latency, with an average of 1.78 ⁇ 0.25 ms, indicating efficient nerve conduction.
  • Group II and Group III showed mean latencies of 2.02 ⁇ 0.40 ms and 2.03 ⁇ 0.34 ms, respectively. Although the difference was not statistically significant, the trend suggested better functional recovery in the autologous transplant group.
  • Table 1 The results of the electrophysiological evaluation are summarized in Table 1.

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Abstract

La présente invention concerne une composition pharmaceutique pour le traitement d'une lésion nerveuse, comprenant des exosomes de lait en tant que principe actif, qui peut traiter rapidement une lésion nerveuse provoquée par un traumatisme grâce à d'excellents effets favorisant la régénération nerveuse sans effets secondaires.
PCT/KR2025/001095 2024-01-19 2025-01-20 Composition pharmaceutique pour le traitement d'une lésion nerveuse comprenant des exosomes de lait en tant que principe actif Pending WO2025155149A1 (fr)

Applications Claiming Priority (2)

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KR20240008751 2024-01-19
KR10-2024-0008751 2024-01-19

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WO2025155149A1 true WO2025155149A1 (fr) 2025-07-24

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KR20210066750A (ko) * 2019-11-28 2021-06-07 한국과학기술연구원 밀크 엑소좀의 새로운 용도
KR20220153271A (ko) * 2021-05-11 2022-11-18 충북대학교 산학협력단 우유로부터 유래된 엑소좀을 유효성분으로 포함하는 흉터 생성 억제용 조성물
WO2024016002A1 (fr) * 2022-07-15 2024-01-18 Virginia Tech Intellectual Properties, Inc. Exosomes dérivés du lait et leurs utilisations

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