US-12622930-B2 - Pharmaceutical composition for preventing or treating brain disease, comprising stem cell-derived exosome surface-modified with compound capable of binding to dopamine receptors or L-amino acid transporters

US12622930B2US 12622930 B2US12622930 B2US 12622930B2US-12622930-B2

Abstract

The present disclosure relates to a pharmaceutical composition for preventing or treating a brain disease, comprising a stem cell-derived exosome surface-modified with a compound capable of binding to dopamine receptors or L-amino acid transporters as an active ingredient. The stem cell-derived exosome according to the present disclosure selectively binds to dopamine receptors (D2) overexpressed as autoreceptors in dopaminergic neurons in the substantia nigra through surface modification. Thereby, local accumulation in dopaminergic neurons is possible. In addition, it was identified that the stem cell-derived exosome exhibited an excellent neuron protective effect and neuron death inhibitory effect. Accordingly, the surface-modified stem cell-derived exosome according to the present disclosure is expected to be usefully used as a composition for preventing or treating a brain disease including Parkinson's disease and Alzheimer's disease.

Inventors

Jae Hyung Park
Dong Gyu JO
Sol SHIN
Jae Hoon SUL

Assignees

Research & Business Foundation Sungkyunkwan University

Dates

Publication Date: 20260512
Application Date: 20230203
Priority Date: 20220203

Claims (8)

1 . A method for treating or alleviating a brain disease, comprising administering to a subject in need thereof a composition comprising, as an active ingredient, a stem cell-derived exosome surface-modified with a compound capable of binding to dopamine receptors or L-amino acid transporters, wherein the surface-modified exosome comprises a linker that binds the compound to the exosome surface, wherein the brain disease is one or more selected from the group consisting of Parkinson's disease, Alzheimer's disease, dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Creutzfeldt-Jakob disease, Pick disease, and Lewy body disease.
2 . The method of claim 1 , wherein the stem cells are one or more selected from the group consisting of adipose-derived stem cells, umbilical cord blood stem cells, bone marrow stem cells, neural stem cells, muscle stem cells, skin stem cells, and amnion stem cells.
3 . The method of claim 1 , wherein the compound capable of binding to dopamine receptors or L-amino acid transporters is dopamine or a dopamine precursor.
4 . The method of claim 3 , wherein the dopamine precursor is one or more selected from the group consisting of levodopa (L-dopa), L-phenylalanine, L-tyrosine, phenylethylamine, and tyramine.
5 . The method of claim 1 , wherein the stem cell-derived exosome has a targeting ability for dopaminergic neurons.
6 . The method of claim 1 , wherein the stem cell-derived exosome has a neuroprotective activity.
7 . The method of claim 1 , wherein the stem cell-derived exosome is surface-modified through one or more chemical bonds selected from the group consisting of ionic bonds, covalent bonds, metal bonds, coordination bonds, hydrogen bonds, and intermolecular forces between exosome surface proteins and the compound capable of binding to dopamine receptors or L-amino acid transporters; or hydrophobic insertion of amphiphilic compound bound to the compound capable of binding to dopamine receptors or L-amino acid transporters into phospholipid bilayer of the exosome.
8 . The method of claim 1 , wherein the compound capable of binding to dopamine receptors or L-amino acid transporters is bound to a surface of the exosome at a dry weight ratio of 1:0.0005 to 0.005 (the exosome:the compound capable of binding to dopamine receptors or L-amino acid transporters) with respect to a dry weight of the exosome.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to and the benefit of Korean Patent Application Nos. 10-2022-0014437 and 10-2023-0013690 filed on Feb. 3, 2022 and Feb. 1, 2023, respectively, and the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND 1. Field of the Invention The present disclosure relates to a pharmaceutical composition for preventing or treating a brain disease, wherein the pharmaceutical composition comprises, as an active ingredient, a stem cell-derived exosome surface-modified with a compound capable of binding to dopamine receptors or L-amino acid transporters. 2. Discussion of Related Art A degenerative brain disease refers to one of the degenerative diseases that develop in the brain with advancing years. It is known that the degenerative brain disease is caused by a decrease in the number of brain cells due to which certain brain cell groups in the brain and spinal cord gradually lose their functions for reasons unknown to date, death of the brain neurons, which are most important for the transmission of information in the brain nervous system, problems in the formation or function of synapses that transmit information between brain neurons, and abnormal symptoms or reduction in electrical activity of the cranial nerves. Examples of representative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Parkinson's disease is a neurodegenerative brain disease caused by a deficiency of dopamine in the nigro-striatal pathway as a result of specific loss of dopaminergic neurons in the substantia nigra in the midbrain area and catecholamine neurons in the brainstem, resulting in motor function abnormalities such as tremors, muscle stiffness, and bradykinesia, in which body movements are slowed down. In the current treatment method, drug treatment and exercise therapy are preceded by symptomatic therapy, and surgery is performed for late patients who do not show appropriate efficacy of drug treatment. Drug treatment relieves symptoms for a while by using dopamine precursors (levodopa) and dopamine agonists to replenish the deficient dopamine and delay the loss of dopamine in the brain, but it does not stop the degeneration and loss of dopaminergic neurons. Therefore, a fundamental treatment method is required. Exosomes are membrane vesicles with a size of 50-200 nm that are secreted from cells and are mostly present in bodily fluids including blood and urine, carry cell-specific constituents accounting for unique biological functions of cells of origin (donor cell), and include various water-soluble proteins, peripheral proteins, and transmembrane protein components in addition to phospholipids, mRNA, miRNA, and DNA. Exosomes have lipid bilayers that are the same phospholipid bilayer structure as in source cells (donor cells), and are compositions of substances extracellularly excreted by cells, delivering physiologically active substances to receptor cells and acting as signal transduction mediators that control cell functions such as cell-cell communication and cellular immune intervention. In particular, it is known that “stem cell-derived exosomes” secreted from stem cells contain various physiologically active factors and genetic materials and may control cell behavior regulation, stem cell differentiation, and tissue regeneration. Transplant therapy using stem cells is currently in the clinical stage, and it is known that the injected stem cells differentiate into dopaminergic neurons to replace damaged neurons or suppress peripheral inflammatory responses to exhibit therapeutic effects. However, in vitro differentiation is possible, but there is an issue that the engraftment rate and differentiation efficiency of transplanted cells are low. Furthermore, there are difficulties in the clinical stage due to limitations such as permanent damage caused by invasive procedures accompanying transplantation of stem cells, risk of cancerization of transplanted cells and intractable immune response, and infection by fetal bovine serum used in cell culture stage. However, stem cell-derived exosomes are known to be rich in bioactive factors secreted from stem cells, so they can replace the functions of parent cells, have a cell membrane-like structure, have high biocompatibility, and may pass through the blood-brain barrier. It is expected to form a new treatment method paradigm that may solve the issues of existing stem cell-based therapeutic agents, such as low survival rate and differentiation rate of cells injected into the body and tissue calcification. However, in general, when injected into the body, less than 1% of Naïve exosomes reach the brain, so an efficient intracerebral delivery method is required to use exosome therapeutic agents for brain diseases. In this regard, the present inventors, as a method for increasing the efficiency and efficacy of drugs through effici