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KR-102963975-B1 - Phamaceutical composition for preventing or treating brain disease, comprising surface-modified exosome derived from stem cell with compounds capable of binding to dopamine receptors or L-amino acid transporters

KR102963975B1KR 102963975 B1KR102963975 B1KR 102963975B1KR-102963975-B1

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of brain diseases comprising, as an active ingredient, a stem cell-derived exosome surface-modified with a compound capable of binding to a dopamine receptor or an L-amino acid transporter. It was confirmed that the stem cell-derived exosome according to the present invention selectively binds to a dopamine receptor (D2) that is overexpressed as a self-receptor in dopaminergic neurons within the substantia nigra through surface modification, enabling local accumulation in dopaminergic neurons and exhibiting excellent neuroprotective effects and neuronal cell death inhibition effects. Accordingly, the surface-modified stem cell-derived exosome according to the present invention is expected to be usefully utilized as a composition for the prevention or treatment of brain diseases, including Parkinson's disease and Alzheimer's disease.

Inventors

  • 박재형
  • 조동규
  • 신솔
  • 설재훈

Assignees

  • 성균관대학교산학협력단

Dates

Publication Date
20260513
Application Date
20230201
Priority Date
20220203

Claims (13)

  1. A pharmaceutical composition for the prevention or treatment of brain diseases comprising adipose stem cell-derived exosomes as an active ingredient, The above-mentioned adipose stem cell-derived exosomes are characterized by having their surface modified with a compound capable of binding to a dopamine receptor or an L-amino acid transporter, and The above compound is dopamine, and A pharmaceutical composition for the prevention or treatment of a brain disease, wherein the brain disease is Parkinson's disease.
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  5. In paragraph 1, A pharmaceutical composition for the prevention or treatment of brain diseases, characterized in that the above-mentioned adipose stem cell-derived exosomes have the ability to target dopaminergic neurons.
  6. In paragraph 1, A pharmaceutical composition for the prevention or treatment of brain diseases, characterized in that the above-mentioned adipose stem cell-derived exosomes have neuroprotective activity.
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  8. In paragraph 1, The above-mentioned adipose stem cell-derived exosomes comprise an exosome surface protein; and one or more chemical bonds selected from the group consisting of ionic bonds, covalent bonds, metallic bonds, coordinate bonds, hydrogen bonds, and intermolecular forces of a compound capable of binding to a dopamine receptor or an L-amino acid transporter, or A pharmaceutical composition for the prevention or treatment of brain diseases, characterized by a surface modified through hydrophobic insertion into an exosome phospholipid bilayer of an amphiphilic compound bound to a compound capable of binding to a dopamine receptor or an L-amino acid transporter.
  9. In paragraph 1, A pharmaceutical composition for the prevention or treatment of brain diseases, characterized in that the compound capable of binding to the dopamine receptor or L-amino acid transporter is bound to the surface of the exosome in a dry weight ratio of 1:0.0005 to 0.005 (exosome: compound capable of binding to the dopamine receptor or L-amino acid transporter) relative to the dry weight of the exosome.
  10. A method for preparing dopamine-surfaced adipose stem cell-derived exosomes comprising the following steps: (a) a step of extracting exosomes from adipose stem cells; and (b) Step of adding dopamine and stirring.
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  12. As adipose stem cell-derived exosomes whose surface is modified with a compound capable of binding to a dopamine receptor or an L-amino acid transporter, Characterized by having targeting ability for dopaminergic neurons and neuroprotective activity, The above compound is an exosome, which is dopamine.
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Description

Pharmaceutical composition for preventing or treating brain disease, comprising surface-modified exosome derived from stem cell with compounds capable of binding to dopamine receptors or L-amino acid transporters The present invention relates to a pharmaceutical composition for the prevention or treatment of brain diseases comprising stem cell-derived exosomes surface-modified with a compound capable of binding to a dopamine receptor or an L-amino acid transporter as an active ingredient. Degenerative brain disease is a type of brain-related degenerative disease that occurs with aging. It is known to be caused by causes currently unknown, in which specific groups of brain cells in the brain and spinal cord gradually lose their function and the number of brain cells decreases; it is triggered by the death of neurons, which are crucial for information transmission in the nervous system; problems with the formation or function of synapses that transmit information between neurons; and abnormal symptoms or a decrease in the electrical activity of brain neurons. Representative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Parkinson's disease is a neurodegenerative brain disorder caused by a deficiency of dopamine in the nigro-striatal pathway resulting from the specific loss of dopaminergic neurons in the substantia nigra of the midbrain and catecholamine neurons in the brainstem. This leads to motor dysfunction, including tremors, muscle rigidity, and bradykinesia (slowness of movement). Current treatments prioritize symptomatic therapy through medication and exercise, with surgery performed on late-stage patients for whom medication is ineffective. While medication utilizes dopamine precursors (levodopa) and dopamine agonists to replenish deficient dopamine and delay brain loss, thereby alleviating symptoms for a period, it fails to halt the degeneration and loss of dopaminergic neurons, necessitating a fundamental cure. Meanwhile, exosomes are membrane vesicles with a size of 50-200 nm secreted from cells, mostly found in body fluids including blood and urine, and contain cell-specific components that reflect the biological functions characteristic of the originating cell (donor cell), and include various water-soluble proteins, extrinsic proteins, and transmembrane protein components in addition to phospholipids, mRNA, miRNA, and DNA. The lipid bilayer of exosomes has a phospholipid bilayer structure similar to that of the originating cell (donor cell) and acts as a signaling mediator that regulates cell functions, such as cell-to-cell communication and cellular immunity mediation, by delivering physiologically active substances to recipient cells as components of substances secreted extracellularly by the cell. In particular, 'stem cell-derived exosomes' secreted from stem cells are known to contain various physiologically active factors and genetic material, which can control cell behavior, stem cell differentiation, and tissue regeneration. Stem cell transplantation therapy is currently in the clinical stage, where it is known to exert therapeutic effects by having injected stem cells differentiate into dopaminergic neurons to replace damaged nerve cells or suppress peripheral inflammatory responses. However, while differentiation is possible in vitro, there are issues regarding the low engraftment rate and differentiation efficiency of transplanted cells. Furthermore, the technology faces difficulties in the clinical phase due to limitations such as permanent damage caused by the invasive procedures involved in stem cell transplantation, risks of carcinogenesis and intractable immune responses in transplanted cells, and infection caused by fetal bovine serum used in the cell culture stage. In contrast, stem cell-derived exosomes are known to possess a rich content of bioactive factors secreted by stem cells, allowing them to replace the functions of progenitor cells. Furthermore, they exhibit high biocompatibility due to their cell membrane-like structure and are capable of crossing the blood-brain barrier. Consequently, they are expected to establish a new therapeutic paradigm capable of resolving the issues associated with existing stem cell-based therapies, such as low cell viability and differentiation rates after injection, as well as tissue calcification. However, since generally less than 1% of naive exosomes reach the brain upon injection, an efficient intracerebral delivery method is required to utilize exosome therapies for brain diseases. Accordingly, the inventors intended to enable local accumulation in dopaminergic neurons by selectively binding to dopaminergic receptors (D2) that are overexpressed as autoreceptors in dopaminergic neurons within the substantia nigra, as a method to increase the efficiency and efficacy of drugs through efficient intracerebral drug delivery in the treatment of brain diseases. FIG. 1 is a di