Compositions and methods for treating kidney disease and other diseases

Abstract

This specification describes a method for treating kidney disease, comprising administering a cell-derived product to the patient's perirenal adipose tissue (PRAT) in patients requiring treatment for kidney disease. Optionally, the cell-derived product is a plurality of mesenchymal stromal cells. Other diseases, including liver disease, cardiovascular disease, inflammatory disease, fibrous disease, autoimmune disease, and visceral disease, can be treated using this method.

Description

[Technical Field]

[0001] [Cross-reference of related applications]

[0001] This asserts the interests of U.S. Provisional Patent Application No. 63 / 505,434, filed on 1 June 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] [Field]

[0002] An aspect of the present invention relates to a method for administering a bioactive substance to the kidneys of a patient who requires a bioactive substance for the treatment of kidney disease, liver disease, and cardiovascular disease.

[0003] [background]

[0003] Chronic kidney disease (CKD) has evolved from a global public health problem into a growing pandemic characterized by increasing prevalence, high morbidity, and high mortality. Glomerular filtration rate (GFR) and albuminuria are the most accurate indicators of kidney function, and low GFR and high albuminuria increase the risk of renal failure requiring renal replacement therapy (RRT), as well as cardiovascular disease, anemia, mineral and bone disorders, and other complications.

[0004]

[0004] Regardless of the underlying etiology, CKD inevitably progresses, leading to irreversible nephron deficiency, end-stage renal disease (ESRD), and / or premature death. Factors contributing to the progression of CKD include parenchymal cell loss, chronic inflammation, fibrosis, and decreased renal regenerative capacity. Current treatments have limited effectiveness and only slow the progression of the disease, highlighting the need to develop new therapies to stop or reverse its progression.

[0005]

[0005] Mesenchymal stromal (stem) cells (MSCs) are stem cells that exhibit potent immunomodulatory properties. MSCs can influence many different immune cell subtypes in both the innate and adaptive immune systems. Numerous laboratory and clinical studies over the past 30 years have demonstrated that MSCs can suppress the proliferation of T cells, B cells, natural killer cells, and dendritic cells in a dose-dependent manner. Furthermore, MSCs have the ability to induce macrophages into a highly immune-tolerant (M2) phenotype characterized by surrogate activation. The cytokine secretion profiles of T cells and B cells can also be significantly altered to a less inflammatory and fibrotic phenotype upon incubation with MSCs, potentially contributing further to the observed immunosuppressive properties.

[0006] [overview]

[0006] This specification describes a method for treating kidney disease, comprising administering a cell-derived product to the perirenal adipose tissue (PRAT) of a patient requiring treatment for kidney disease. Optionally, the cell-derived product is a plurality of mesenchymal stromal cells. Other diseases, such as liver disease, cardiovascular disease, inflammatory disease, fibrous disease, autoimmune disease, and visceral disease, can be treated using this method. [Brief explanation of the drawing]

[0007] [Figure 1] This photograph shows the kidney of a mouse that has been administered methylene blue to a PRAT (Phaseolar Artery Artery), demonstrating that the dye remains in the PRAT and is delivered to the kidney, but does not leak into the surrounding tissue. [Figure 2] This figure shows the levels of various biomarkers in mouse PRAT and / or kidney tissue compared to control mice in an aristolochic acid (AA) induction model of renal disease in which umbilical cord mesenchymal stromal cells (UC-MSCs) were administered to mouse PRAT, where Arg1 represents arginase 1, PBS represents phosphate-buffered saline, and RK represents the right kidney. [Figure 3] This figure shows the effect of UC-MSC administered to PRAT mice on serum creatinine compared to control mice. [Figure 4A] This figure compares the effects of two different doses (0.5 × 10⁶ cells and 1 × 10⁶ cells) of UC-MSCs administered to mouse PRAT on blood glucose levels (4A), urinary creatinine levels (4B), urinary urea levels (4C), and neutrophil gelatinase-associated lipocalin (Ngal) levels (4D) compared to control mice in a high-fat diet model. HFD stands for high-fat diet, M stands for 1 million cells, and ND stands for normal diet. [Figure 4B] This figure compares the effects of two different doses (0.5 × 10⁶ cells and 1 × 10⁶ cells) of UC-MSCs administered to mouse PRAT on blood glucose levels (4A), urinary creatinine levels (4B), urinary urea levels (4C), and neutrophil gelatinase-associated lipocalin (Ngal) levels (4D) compared to control mice in a high-fat diet model. HFD stands for high-fat diet, M stands for 1 million cells, and ND stands for normal diet. [Figure 4C] This figure compares the effects of two different doses (0.5 × 10⁶ cells and 1 × 10⁶ cells) of UC-MSCs administered to mouse PRAT on blood glucose levels (4A), urinary creatinine levels (4B), urinary urea levels (4C), and neutrophil gelatinase-associated lipocalin (Ngal) levels (4D) compared to control mice in a high-fat diet model. HFD stands for high-fat diet, M stands for 1 million cells, and ND stands for normal diet. [Figure 4D] This figure compares the effects of two different doses (0.5 × 10⁶ cells and 1 × 10⁶ cells) of UC-MSCs administered to mouse PRAT on blood glucose levels (4A), urinary creatinine levels (4B), urinary urea levels (4C), and neutrophil gelatinase-associated lipocalin (Ngal) levels (4D) compared to control mice in a high-fat diet model. HFD stands for high-fat diet, M stands for 1 million cells, and ND stands for normal diet. [Figure 5A]This figure shows the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of the pro-inflammatory markers interleukin-6, IL6 (5A), tumor necrosis factor alpha, TNFa (5B), CC chemokine 2, CCL2 (5C), and connexin 43, C×43 (5D), as well as the relative expression of the renal fibrosis-inducing markers fibronectin-1, FN1 (5E), and collagen 1A1, Col1A1 (5F). [Figure 5B] This figure shows the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of the pro-inflammatory markers interleukin-6, IL6 (5A), tumor necrosis factor alpha, TNFa (5B), CC chemokine 2, CCL2 (5C), and connexin 43, C×43 (5D), as well as the relative expression of the renal fibrosis-inducing markers fibronectin-1, FN1 (5E), and collagen 1A1, Col1A1 (5F). [Figure 5C] This figure shows the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of the pro-inflammatory markers interleukin-6, IL6 (5A), tumor necrosis factor alpha, TNFa (5B), CC chemokine 2, CCL2 (5C), and connexin 43, C×43 (5D), as well as the relative expression of the renal fibrosis-inducing markers fibronectin-1, FN1 (5E), and collagen 1A1, Col1A1 (5F). [Figure 5D] This figure shows the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of the pro-inflammatory markers interleukin-6, IL6 (5A), tumor necrosis factor alpha, TNFa (5B), CC chemokine 2, CCL2 (5C), and connexin 43, C×43 (5D), as well as the relative expression of the renal fibrosis-inducing markers fibronectin-1, FN1 (5E), and collagen 1A1, Col1A1 (5F). [Figure 5E]This figure shows the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of the pro-inflammatory markers interleukin-6, IL6 (5A), tumor necrosis factor alpha, TNFa (5B), CC chemokine 2, CCL2 (5C), and connexin 43, C×43 (5D), as well as the relative expression of the renal fibrosis-inducing markers fibronectin-1, FN1 (5E), and collagen 1A1, Col1A1 (5F). [Figure 5F] This figure shows the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of the pro-inflammatory markers interleukin-6, IL6 (5A), tumor necrosis factor alpha, TNFa (5B), CC chemokine 2, CCL2 (5C), and connexin 43, C×43 (5D), as well as the relative expression of the renal fibrosis-inducing markers fibronectin-1, FN1 (5E), and collagen 1A1, Col1A1 (5F). [Figure 6A] Figures 6A, 6B, and 6D show the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of pro-inflammatory markers (PRAT) and the relative expression of anti-inflammatory markers (PRAT) (Figure 6C), where IL1b represents interleukin 1b and KIM1 represents kidney injury molecule 1. [Figure 6B] Figures 6A, 6B, and 6D show the effects of administering two different doses of UC-MSC to the PRAT of mice fed a high-fat diet on the relative expression of pro-inflammatory markers (PRAT) and the relative expression of anti-inflammatory markers (PRAT) (Figure 6C), where IL1b represents interleukin 1b and KIM1 represents kidney injury molecule 1. [Figure 6C]Figure showing the effect of two different doses of UC-MSCs on the reduction of the relative expression of pro-inflammatory markers (Figs. 6A, 6B, and 6D) and the increase in the relative expression of anti-inflammatory markers (Fig. 6C) in the PRAT of high-fat diet-fed mice after administration to the PRAT, where IL1b means interleukin 1b and KIM1 means kidney injury molecule 1. [Figure 6D] Figure showing the effect of two different doses of UC-MSCs on the reduction of the relative expression of pro-inflammatory markers (Figs. 6A, 6B, and 6D) and the increase in the relative expression of anti-inflammatory markers (Fig. 6C) in the PRAT of high-fat diet-fed mice after administration to the PRAT, where IL1b means interleukin 1b and KIM1 means kidney injury molecule 1. [Figure 7A] Figure showing the effect of two different doses of UC-MSCs on the reduction of the relative expression of pro-inflammatory markers (7A) and fibrosis-inducing markers (7B) in the liver after administration to the PRAT of high-fat diet-fed mice. [Figure 7B] Figure showing the effect of two different doses of UC-MSCs on the reduction of the relative expression of pro-inflammatory markers (7A) and fibrosis-inducing markers (7B) in the liver after administration to the PRAT of high-fat diet-fed mice. Detailed description

[0008]

[0014] Terms

[0015] Cell product: A cell product includes cells that have been shown to be effective in the treatment or alleviation of inflammatory conditions or fibrosis. Mesenchymal stromal cells (MSCs) are an example of such cells. Cell products also include products produced by such cells, such as exosomes or extracellular vesicles produced by MSCs.

[0009]

[0016] Treatment: Treatment means a therapeutic intervention that improves the signs or symptoms of a disease or condition after it has begun to develop.

[0010]

[0017] Unless otherwise indicated, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is to be construed as including "and" unless the context clearly dictates otherwise. All base sizes or amino acid sizes, and all molecular weights or molecular mass values given for a nucleic acid or polypeptide are approximate values and are further understood to be provided for illustrative purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The term "comprises" means "includes." The abbreviation "e.g." is derived from the Latin exempli gratia and is used herein to indicate non-limiting examples. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[0011]

[0018] In case of conflict, this specification, including explanations of terms, will control. Further, the materials, methods, and examples are illustrative only and not limiting.

[0012]

[0019] Perirenal adipose tissue (PRAT), a component of visceral adipose tissue, has recently been recognized as an important factor contributing to the maintenance of cardiovascular and renal homeostasis. PRAT consists of a mixture of white adipocytes and both dormant and active brown adipocytes and is a complex microenvironment associated with preadipocytes, sympathetic nerve endings, vascular structures, and various types of inflammatory cells. Given its location in the vicinity of the kidney, PRAT is considered a distinct visceral fat deposit in terms of specific anatomical features related to angiogenesis and innervation.

[0013]

[0020] The inventors have discovered that administration via PRAT may be advantageous compared to other methods of administering cell products such as umbilical cord MSCs (UC-MSCs). Administration via PRAT may be associated with increased therapeutic efficacy for renal disease compared to known methods of administration (such as subcutaneous and intravenous administration). Furthermore, PRAT administration allows for a lower dose of the administered cell product compared to conventional methods of administration without reducing its activity. Another advantage of PRAT administration is that it may result in lower systemic exposure to the administered treatment and thus higher safety compared to other treatments such as intrarenal administration.

[0014]

[0021] According to a preferred embodiment, UC-MSCs are administered to patients in need of UC-MSCs via PRAT. MSCs from other sources such as placenta, adipose tissue, peripheral blood, and bone marrow may be used depending on the embodiment.

[0015]

[0022] According to one embodiment, the cell products administered to patients in need are multiple exosomes or extracellular vesicles (EVs). Optionally, the exosomes or extracellular vesicles are obtained from MSCs, preferably UC-MSCs. Exosomes and EVs are secreted by MSCs and may have similar therapeutic effects to those of parent cells.

[0016]

[0023] In addition to naturally occurring exosomes secreted by cells such as MSCs, exosomes and extracellular vesicles (EVs) containing active pharmaceutical or biological components may be prepared and administered to patients in need. Exogenous drug loading methods act passively by binding the drug to the exosome or extracellular vesicle (EV) lipid bilayer after incubation, attaching the therapeutic agent to the exosome / EV surface, and then temporarily opening the exosome / EV membrane by mechanical or chemical techniques to diffuse the compound into the vesicle. The most common approaches to temporarily make the membrane permeable include sonication, electroporation, saponin treatment, and passive incubation. According to one embodiment, the exosome / EV contains an active pharmaceutical component selected from the group consisting of sodium-glucose cotransporter-2 (SGLT2) inhibitors, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and mineralocorticoid receptor antagonists. Exemplary SGLT2 inhibitors include, but are not limited to, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Exemplary ARBs are selected from the group consisting of candesartan, valsartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, and fimasartan. Exemplary ACE inhibitors are selected from the group consisting of captopril, enalapril, lisinopril, benazepril, hosinopril, quinapril, ramipril, perindopril, moexipril, trandolapril, alacepril, zofenopril, imidapril, and cilazapril. Exemplary mineralocorticoid receptor antagonists are selected from the group consisting of mexrenone, finerenone, canrenone, eplerenone, and spironolactone. Free or drug-loaded exosomes can be formulated as the following sterile injectable dosage forms for perirenal administration.(a) Hydrophilic formulations containing buffers, electrolytes to adjust isotonicity, sugars, glycols, amino acids, antioxidants, preservatives, polymer stabilizers, surfactants, peptides, and albumin; (b) Hydrophilic hydrogels containing cellulose-derived polymers such as methylcellulose, ethylcellulose, and hydroxypropylmethylcellulose, hyaluronic acid, polysaccharides, gums, heat-sensitive polymers such as poloxamer, and polyvinyl alcohol; (c) Lipid-based formulations containing ultra-refined vegetable oils, phospholipids, polyethylene glycol derivatives, and glycerides.

[0017]

[0024] According to one embodiment, the amount of cell products administered per PRAT dose is an effective amount for showing improvement in the symptoms or markers of renal disease. In the case of MSC administration, the amount administered is preferably up to 500 million cells. In the case of exosomes / EV, the amount administered is 1 × 10⁶ per dose. 9 From 1 x 10 12 Particles between individuals are preferable.

[0018]

[0025] Various types of kidney disease can be treated by the embodiments. According to one embodiment, the kidney disease is a chronic kidney disease. Optionally, the kidney disease is an end-stage kidney disease. The methods described herein can be used not only for the treatment of kidney disease but also for the treatment of comorbidities of kidney disease. Such comorbidities include, but are not limited to, hypertension, diabetes, and obesity. Optionally, patients suffering from kidney disease who require such treatment may be treated with cell products administered via PRAT administration if the patient has a disease selected from the group consisting of Fabry disease, cystinosis, glomerulonephritis, IgA nephropathy, lupus nephritis, systemic lupus erythematosus, atypical hemolytic uremic syndrome, renal fibrosis, nephrogenic systemic fibrosis, focal segmental glomerulosclerosis (FSGS), APOL1 nephropathy, or polycystic kidney disease.

[0019]

[0026] According to one embodiment, PRAT administration may be performed using ultrasound guidance or laparoscopy. Optionally, PRAT administration may be performed using augmented reality.

[0020]

[0027] The treatments described herein may contribute to the improvement of the disease. Optionally, improvement may be evident in the following cases: a reduction in inflammatory or fibrotic biomarkers, a delay in the deterioration of GFR, maintenance or improvement of GFR, and a decrease in serum and urinary creatinine, urea, N-gal, and blood glucose levels.

[0021]

[0028] This specification describes compositions for use in the treatment of a disease, according to certain embodiments, by a method for treating a subject suffering from renal disease, comprising administering a cell product to the perirenal adipose tissue of the subject in an amount effective in showing improvement of the symptoms or markers of renal disease in the subject. Optionally, the cell product comprises a plurality of mesenchymal stromal cells (MSCs). Optionally, the MSCs are of umbilical cord origin. Optionally, the cell product comprises extracellular vesicles or exosomes. Optionally, the extracellular vesicles or exosomes contain an active ingredient selected from the group consisting of sodium-glucose cotransporter-2 (SGLT2) inhibitors, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and mineralocorticoid receptor antagonists. Optionally, the amount of MSCs administered is 10 million to 100 million cells per ml. Optionally, the amount of MSCs administered is up to 500 million cells per dose. Participants are randomly selected from the following groups to have one of the following diseases: chronic kidney disease, end-stage renal disease, Fabry disease, cystinosis, glomerulonephritis, IgA nephropathy, lupus nephritis, systemic lupus erythematosus, atypical hemolytic uremic syndrome, renal fibrosis, nephrogenic systemic fibrosis, focal segmental glomerulosclerosis (FSGS), APOL1 nephropathy, and polycystic kidney disease. Participants are randomly selected from the following groups to have one of the following comorbidities related to renal disease: hypertension, diabetes mellitus, and obesity.

[0022]

[0029] This specification further describes a method for treating a subject suffering from cardiovascular disease, according to embodiments, which includes administering to the perirenal adipose tissue of the subject an amount of cell product effective in showing improvement in the symptoms or markers of cardiovascular disease in the subject.

[0023]

[0030] This specification further describes, according to one embodiment, a method for treating a subject suffering from an inflammatory or fibrotic disease of the liver, comprising administering to the perirenal adipose tissue of the subject an amount of a cell product effective in showing improvement of the symptoms or markers of the inflammatory or fibrotic disease of the liver in the subject.

[0024]

[0031] This specification further describes, according to one embodiment, a method for treating a subject suffering from an autoimmune disease, comprising administering to the perirenal adipose tissue of the subject an amount of a cell product effective in showing improvement of the symptoms or markers of the autoimmune disease in the subject.

[0025]

[0032] This specification further describes, according to one embodiment, a method for treating a subject suffering from a visceral disease, comprising administering to the perirenal adipose tissue of the subject an amount of a cell product effective in showing improvement of the symptoms or markers of the visceral disease in the subject. [Examples]

[0026]

[0033] The following examples are provided to illustrate certain features and / or embodiments. These examples should not be construed as limiting the disclosure to the specific features or embodiments described.

[0027]

[0034] Example 1: Evaluation of perirenal adipose tissue (PRAT) administration in mice in an aristolochic acid (AA)-induced renal disease model.

[0035] An in vivo study of PRAT administration was conducted in mice receiving PRAT. A single dose of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) via PRAT was administered to a mouse model of AA-induced nephropathy.

[0028]

[0036] Aristolochic acid is a nephrotoxin derived from plants of the Aristolochiaceae family. The model was conducted using 16-week-old C57BL6 male mice. To induce a disease-like state similar to acute kidney injury, mice were intraperitoneally (IP) injected with 4 milligrams of AA per kilogram (mg / kg) once a week on days 1, 7, 14, and 21. Treatment was administered in the form of a 50-microliter injection into the PRAT area of ​​the right kidney on day 24, three days after the last injection of AA.

[0029]

[0037] Four groups of mice were used in the study. Group 1 was given 5 × 10⁶ mice dissolved in PBS buffer. 6 Group 1 received a single injection of UC-MSCs in PRAT. Group 2 received a single injection of PBS in PRAT. Group 3 was untreated and received AA alone as a control. Group 4 consisted of untreated mice in which no disease symptoms had been induced.

[0030]

[0038] Serum was collected and creatinine and various biomarkers were evaluated. All mice were observed until day 54, the end of the study. At the end of the study, the animals were euthanized, and the PRAT and associated kidneys were collected. Fibrosis and renal inflammation were determined by histopathological examination (H&E and Masson's trichrome staining). The expression of inflammation and fibrosis markers was determined by RT-qPCR.

[0031]

[0039] Administration of UC-MSCs to PRAT induced changes in adipokine expression within PRAT, as well as in tissue and serum biomarker levels. As shown in Figures 2A and 2B, respectively, upregulation of Arg1, a marker of M2 state, anti-inflammatory, proliferative, and healing-supporting phenotypes, was observed in both PRAT and the kidney. Furthermore, a relative decrease in adiponectin expression in PRAT was shown, along with a relative increase in irisin expression (Figures 2C and 2D). Irisin is released from cardiomyocytes during physical activity and functions as a bridge between muscle and other tissues and organs. Two N-glycan molecules constitute a key part of the irisin glycoprotein and control adipocyte browning, which is irisin's most important function. The study confirmed the multifunctional role of irisin and its beneficial effects on homeostasis in the body. Irisin reduces systemic inflammation, maintains the balance between bone resorption and bone formation, and modulates metabolic processes and nervous system function. It suppresses the expression and release of pro-inflammatory cytokines in obese individuals and alleviates inflammation in adipose tissue. Furthermore, the literature suggests that high levels of irisin may have beneficial effects on the cardiovascular system. Systemically, PRAT administration to UC-MSCs induced a slight decrease in serum creatinine levels (Figure 3). Histological evaluation of the kidneys and PRAT revealed no renal toxicity after PRAT injection in UC-MSCs, supporting the safety of this approach.

[0032]

[0040] Administration of UC-MSCs to PRAT induced both local anti-inflammatory effects (induction of Arg1 in PRAT and the kidney) and endocrine effects in PRAT that may indicate a more general systemic anti-inflammatory metabolic state (induction of irisin and reduction of adiponectin). Furthermore, a slight decrease in serum creatinine levels supports the induction of renal healing processes resulting from the anti-inflammatory paracrine effect of UC-MSCs injected into PRAT.

[0033]

[0041] Example 2A: Administration of methylene blue (MB) to the perirenal adipose tissue of healthy mice.

[0042] A 1% solution of methylene blue was injected into the perirenal adipose tissue of healthy mice. After 24 hours, the mice were euthanized, and as shown in Figure 1, the kidneys were cut in the direction of the arrow for visual inspection. At the time of inspection, blue coloring was observed only in the kidney tissue and PRAT, as indicated by the blue arrow, and not in the surrounding tissues. This indicates that PRAT-specific delivery can be used for the treatment and delivery of the kidneys.

[0034]

[0043] Example 2B: Administration of human UC-MSCs to mice

[0044] Using the procedure described in Example 2A, 2×10 6 human UC-MSCs were injected into the PRAT of healthy mice. After observing for one week, the mice were found to be in good condition.

[0035]

[0045] Example 3: Therapeutic effect of UC-MSCs via PRAT in a model of obesity-related nephropathy in C57BL6 mice

[0046] 0.5×10 6 or 1×10 6 A single administration of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) to a high-fat diet (HFD) obesity-related nephropathy model of C57BL6 mice via injection into the perirenal adipose tissue (PRAT) was performed.

[0036]

[0047] Male C57BL / 6J mice at 8 weeks of age were fed a high-fat diet (HFD, 60% fat) for 8 weeks. As a control group, male C57BL / 6J mice of the same age were fed a standard laboratory normal diet (ND, 14% fat). At the 8th week, 0.5×10 6 or 1×10 6 UC-MSCs, or only PBS, suspended in PBS were injected into the right PRAT. The mice in the HFD group continued to receive the HFD for an additional 6 weeks. At the 14th week, the mice were euthanized, and samples of the kidneys, PRAT, liver, and heart were collected for analysis. 0.5×10 6 and / or 1×10 6Administration of UC-MSCs induced effects at both systemic and local tissue levels. As shown in Figure 4A, HFD mice had elevated blood glucose levels compared to normal-fed mice (an increase of approximately 30%, from approximately 150 mg / dL to 200 mg / dL). Administration of both dose levels of UC-MSCs within PRAT lowered blood glucose levels by approximately 120–130 mg / dL, 20–30 units below the control baseline (ND, normal diet).

[0037]

[0048] Furthermore, HFD mice showed increased levels of urinary creatinine and urea, indicating impaired normal renal function. As shown in Figures 4B and 4C, 0.5 × 10⁻⁶ 6 Administration of UC-MSCs into PRAT reduced the levels of these metabolic markers below control levels. Neutrophil gelatinase-associated lipocalin (Ngal), a 21kD protein of the lipocalin superfamily, is a component of innate immunity against bacterial infections and is expressed by immune cells, hepatocytes, and renal tubular cells in various disease states. Because Ngal is protease-resistant, it can be readily detected in urine. This marker has emerged as a potential biomarker for diabetic nephropathy due to its association with kidney injury and its ability to provide early signs of renal impairment. As shown in Figure 4D, both doses of UC-MSC reduced elevated Ngal levels to control levels.

[0038]

[0049] Furthermore, as shown in Figures 5A-F, administration of UC-MSCs into PRAT resulted in a relative decrease in the expression of pro-inflammatory markers IL6, TNFa, CC chemokine 2 (CCL2), and connexin 43 (C×43), as well as pro-fibrotic markers fibronectin 1 (FN1) and collagen 1A1 (Col1A1). In the PRAT itself, ipsilateral (right kidney (indicated as "R") and / or contralateral (left kidney (indicated as "L")) administration of UC-MSCs induced a decrease in the relative expression of IL1b (Figure 6A) and CCL2 (a pro-inflammatory marker, Figure 6B), and a sharp decrease in the relative expression of kidney injury molecule 1 (KIM1, Figure 6D), a transmembrane glycoprotein expressed by proximal tubular cells that is recognized as an early, highly sensitive, and specific biomarker of kidney injury. In contrast, as shown in Figure 6C, UC-MSC administration into the PRAT induced an increase in the relative expression of the anti-inflammatory factor irisin.

[0039]

[0050] The relative expression of CCL2 and Col1A1 in the liver was also examined. As shown in Figures 7A and 7B, UC-MSC administered to PRAT caused a decrease in the relative expression of these two markers, further supporting the systemic anti-inflammatory and anti-fibrotic effects of this method in organs other than the kidney, such as the liver.

[0040]

[0051] Given that there are numerous embodiments to which the principles of the disclosed invention can be applied, it should be recognized that the exemplary embodiments are merely preferred examples of the invention and do not limit its scope. Rather, the scope of the invention is defined by the following claims. Accordingly, the inventors assert that everything contained in these claims and their intent is their invention.

Claims

1. A composition comprising cell products for use in the treatment of a subject suffering from renal disease, wherein the use comprises administering to the perirenal adipose tissue of the subject an amount effective in showing improvement of the symptoms or markers of renal disease in the subject.

2. The composition for use according to claim 1, wherein the cell product comprises a plurality of mesenchymal stromal cells (MSCs).

3. The composition for use according to claim 2, wherein the MSCs are of umbilical cord origin.

4. The composition for use according to claim 1, wherein the cell product comprises an extracellular vesicle or an exosome.

5. The composition for use according to claim 4, wherein the extracellular vesicles or exosomes contain an active ingredient selected from the group consisting of sodium-glucose cotransporter-2 (SGLT2) inhibitors, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and mineralocorticoid receptor antagonists.

6. The composition for use according to claim 2, wherein the amount of MSCs administered is 10 million to 100 million cells per 1 ml.

7. The composition for use according to any one of claims 2, 3, or 6, wherein the amount of MSCs administered is up to 500 million cells per dose.

8. The composition for use according to any one of claims 1 to 7, wherein the subject suffers from a disease selected from the group consisting of chronic kidney disease, end-stage renal disease, Fabry disease, cystinosis, glomerulonephritis, IgA nephropathy, lupus nephritis, systemic lupus erythematosus, atypical hemolytic uremic syndrome, renal fibrosis, nephrogenic systemic fibrosis, focal segmental glomerulosclerosis (FSGS), APOL1 nephropathy, and polycystic kidney disease.

9. The composition for use according to any one of claims 1 to 7, wherein the subject suffers from a comorbidity of renal disease selected from the group consisting of hypertension, diabetes mellitus, and obesity.

10. A composition comprising cell products for use in the treatment of a subject suffering from cardiovascular disease, wherein the use comprises administering to the perirenal adipose tissue of the subject an amount effective in showing improvement of the symptoms or markers of cardiovascular disease in the subject.

11. A composition comprising cell products for use in the treatment of a subject suffering from an inflammatory or fibrotic disease of the liver, wherein the use comprises administering to the perirenal adipose tissue of the subject an amount effective in showing improvement of the symptoms or markers of the inflammatory or fibrotic disease in the subject.

12. A composition comprising cell products for use in the treatment of a subject suffering from an autoimmune disease, wherein the use comprises administering to the perirenal adipose tissue of the subject an amount effective in showing improvement of the symptoms or markers of the autoimmune disease in the subject.

13. A composition comprising cell products for use in the treatment of a subject suffering from an internal organ disease, wherein the use comprises administering to the perirenal adipose tissue of the subject an amount effective in showing improvement of the symptoms or markers of the internal organ disease in the subject.

14. A method for treating a subject suffering from kidney disease, comprising administering a cell product to the perirenal adipose tissue of the subject in an amount effective in showing improvement of the symptoms or markers of kidney disease in the subject.

15. The method according to claim 14, wherein the cell product comprises a plurality of mesenchymal stromal cells (MSCs).

16. The method according to claim 15, wherein the MSC is of umbilical cord origin.

17. The method according to claim 14, wherein the cell product comprises an extracellular vesicle or an exosome.

18. The method according to claim 17, wherein the extracellular vesicle or exosome contains an active ingredient selected from the group consisting of a sodium-glucose cotransporter-2 (SGLT2) inhibitor, angiotensin receptor blocker (ARB), angiotensin-converting enzyme (ACE) inhibitor, and mineralocorticoid receptor antagonist.

19. The method according to claim 15, wherein the amount of MSCs administered is 10 million to 100 million cells per ml.

20. The method according to any one of claims 14, 15, or 19, wherein the amount of MSCs administered is up to 500 million cells per dose.

21. The method according to any one of claims 14 to 20, wherein the subject suffers from a disease selected from the group consisting of chronic kidney disease, end-stage renal disease, Fabry disease, cystinosis, glomerulonephritis, IgA nephropathy, lupus nephritis, systemic lupus erythematosus, atypical hemolytic uremic syndrome, renal fibrosis, nephrogenic systemic fibrosis, focal segmental glomerulosclerosis (FSGS), APOL1 nephropathy, and polycystic kidney disease.

22. The method according to any one of claims 14 to 21, wherein the subject suffers from a comorbidity of renal disease selected from the group consisting of hypertension, diabetes, and obesity.

23. A method for treating a subject suffering from cardiovascular disease, comprising administering to the perirenal adipose tissue of the subject an amount of cell products effective in showing improvement of symptoms or markers of cardiovascular disease in the subject.

24. A method for treating a subject suffering from an inflammatory or fibrotic disease of the liver, comprising administering to the perirenal adipose tissue of the subject an amount of a cell product effective in showing improvement of the symptoms or markers of the inflammatory or fibrotic disease of the liver in the subject.

25. A method for treating a subject suffering from an autoimmune disease, comprising administering to the perirenal adipose tissue of the subject an amount of cell products effective in showing improvement of the symptoms or markers of the autoimmune disease in the subject.

26. A method for treating a subject suffering from an internal organ disease, comprising administering to the perirenal adipose tissue of the subject an amount of cell products effective in showing improvement of the symptoms or markers of the internal organ disease in the subject.

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