US20160058800A1 - Pluripotent stem cell for treatment of chronic kidney disease - Google Patents

Pluripotent stem cell for treatment of chronic kidney disease Download PDF

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US20160058800A1
US20160058800A1 US14/695,872 US201514695872A US2016058800A1 US 20160058800 A1 US20160058800 A1 US 20160058800A1 US 201514695872 A US201514695872 A US 201514695872A US 2016058800 A1 US2016058800 A1 US 2016058800A1
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cells
negative
renal
muse
pluripotent stem
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Masanori Yoshida
Mari Dezawa
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Tohoku University NUC
Clio Inc
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Clio Inc
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Assigned to CLIO, INC., TOHOKU UNIVERSITY reassignment CLIO, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEZAWA, MARI, YOSHIDA, MASANORI
Publication of US20160058800A1 publication Critical patent/US20160058800A1/en
Priority to US15/413,129 priority Critical patent/US10293003B2/en
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    • 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
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
    • A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a cell preparation used in regenerative medicine. More specifically, the present invention relates to a cell preparation containing pluripotent stem cells that are effective for repairing and regenerating renal tissue that has been damaged by renal failure.
  • kidney diseases including chronic glomerular nephritis, diabetic nephropathy and polycystic kidney disease
  • the course of the disease is progressive, and unless treatment is effective, these diseases ultimately result in loss of kidney function, eventually leading to dialysis due to renal failure.
  • dialysis treatment costs for treating kidney diseases exceeds one trillion yen, accounting for roughly 3% of all medical care expenditures, and the number of patients suffering from kidney damage is increasing annually.
  • glomerular epithelial cell disorders refer to disorders in which the glomerular epithelium is subjected to functional or structural damage due to various causes.
  • glomerular epithelial cells are referred to as podocytes, and are highly differentiated cells that line the outer surface of the glomerular basement membrane (GBM).
  • Podocytes are a determinate component of the filtration barrier, and mutations in the genes of nephrin, podocin, ⁇ -actinin-4 and the like have been found to cause kidney disease-associated proteinuria (Schmid, H., et al., J. Am. Soc. Nephrol., Vol. 14, p. 2958-2966 (2003); Mundel, P. & Shankland, S.
  • podocytes regulate glomerular filtration rate in response to changes in perfusion pressure by reacting to changes in pressure in glomerular capillaries (Mundel, P., et al., 2002, supra; Morton, M. J., J. Am. Soc. Nephrol., Vol. 15, p. 2981-2987 (2004); Pavenstadt, H., et al., Physiol. Rev., Vol. 83, p. 253-307 (2003)).
  • glomerular epithelium containing podocytes fulfills an important role in the waste filtration function of the kidneys, it is imperative to prevent disorders of the glomerular epithelium from progressing to renal sclerosis so as not to allow further increases in the number of dialysis patients.
  • kidney diseases are not limited to disorders of the glomerulus, but also include diseases affecting renal tubules. Renal tubules are formed from the proximal renal tubule, the loop of Henle, the distal renal tubule and the renal collecting duct. If an abnormality occurs in the function of the renal tubules for some reason, various diseases may occur throughout the body. Examples of diseases of the proximal renal tubule include Fanconi's syndrome, aminoaciduria and renal glycosuria, while distal renal tubular acidosis is known to be a typical example of a disease of the distal renal tubule.
  • kidney disease As chronic kidney disease progresses, since the functions possessed by a normal kidney are lost, effects extend to various organs throughout the body, typically resulting in uremia. Specific examples of disorders that occur include central nervous system disorders, peripheral nervous system disorders, cardiovascular disorders, gastrointestinal disorders, vision/ophthalmic disorders, blood/coagulation disorders, immune disorders, endocrine disorders, skin disorders, bone/joint disorders, electrolyte disorders and acid-base balance disorders.
  • artificial dialysis for preventing uremia is essential for the treatment of chronic kidney diseases, and kidney transplant is the only radical treatment that ensures a complete recovery.
  • Muse cells multilineage-differentiating stress enduring cells
  • SSEA-3 stage-specific embryonic antigen-3
  • Muse cells were also determined to be able to be concentrated by stimulating mesenchymal cell fractions with various types of stress (WO2011/007900; Li, S., et al., Cancer Gene Therapy, Vol. 12, p.
  • An object of the present invention is to provide a novel medical application to regenerative medicine that uses pluripotent stem cells (Muse cells). More specifically, an object of the present invention is to provide a cell preparation for prevention and/or treatment of chronic kidney disease that contains Muse cells.
  • the inventors of the present invention found that intravascular administration of Muse cells into chronic kidney disease mice resulted in Muse cells accumulating in renal tissue, reconstruction and repair of damaged glomeruli and renal tubules and improvement or recovery of renal function, thereby leading to completion of the present invention.
  • a cell preparation for preventing and/or treating chronic kidney disease containing pluripotent stem cells positive for SSEA-3 isolated from biological mesenchymal tissue or cultured mesenchymal cells.
  • FIG. 4 indicates the results of examining the taking of human Muse cells and non-Muse cells to renal tissue following administration into a caudal vein (after six weeks). In contrast to Muse cells having taken to renal tissue, hardly any of the non-Muse cells took to renal tissue.
  • FIG. 9 indicates the results of examining the mobility of human Muse cells to sites of kidney disease.
  • Muse cells stained with Hoechest 33342 stain were administered into a caudal vein of chronic kidney disease model mice, followed by fixing the renal tissue and observing under a fluorescence microscope 24 hours later.
  • Nuclear-stained Muse cells were identified as spots exhibiting a strong signal (indicated by arrows).
  • Muse cells administered into a caudal vein can be understood to be widely distributed in, for example, glomeruli, renal tubules and interstitium.
  • applicable diseases thereof may be considered to be chronic or acute diseases in tissue such as the glomeruli and renal tubules.
  • chronic kidney diseases include chronic glomerular nephritis, renal sclerosis, diabetic nephropathy, renal cyst, chronic pyelonephritis, rapidly progressive glomerulonephritis, malignant hypertension, SLE nephritis, renal amyloidosis, renal/urinary tract tumors, myeloma, obstructive uropathy, renal gout, renal hypoplasia and renal/urinary tract tuberculosis.
  • Muse cells or cell populations containing Muse cells can be isolated from biological tissue (such as mesenchymal tissue) using antibody to the cell surface marker SSEA-3 alone or using antibody to SSEA-3 and CD105, respectively.
  • biological tissue refers to the biological tissue of a mammal. In the present invention, although an embryo in a development stage prior to a fertilized egg or blastula stage is not included in biological tissue, an embryo in a development stage in or after the fetus or blastula stage, including the blastula, is included.
  • Muse cells have the ability to differentiate into the three germ layers (endoderm, mesoderm and ectoderm) in vitro and in vivo, and by inducing to differentiate by culturing in vitro, for example, can differentiate into skin, liver, nerve, muscle, bone or fat and the like.
  • Muse cells may also demonstrate the ability to differentiate into the three germ layers in the case of transplanting in vivo into testes, for example.
  • Muse cells also have the ability to migrate, graft and differentiate into a damaged organ (such as the heart, skin, spinal cord, liver or muscle) by being transplanted into the body by intravenous injection.
  • self-renewal refers to culturing cells contained in an embryoid body-like cell mass obtained by suspension culturing single Muse cell and allowing them to reform an embryoid body-like cell mass from a single cell again as well as to demonstrate spontaneous differentiation of embryoid body-like cell mass into triploblastic cell lineages on gelatin coated culture. Self-renewal may be carried out for one cycle or repeated for a plurality of cycles.
  • the cell preparation of the present invention is obtained by suspending Muse cells or a cell population containing Muse cells obtained in the aforementioned (1) in physiological saline or a suitable buffer (such as phosphate-buffered physiological saline).
  • physiological saline or a suitable buffer such as phosphate-buffered physiological saline.
  • cells may be cultured prior to cell transplant and allowed them to proliferate until a prescribed cell concentration is obtained.
  • Muse cells do not undergo neoplastic transformation, there is little likelihood of the cells becoming malignant even if cells recovered from biological tissue are contained that have still not differentiated, thereby making them safe.
  • DMSO dimethylsulfoxide
  • serum albumin for protecting the cells, or antibiotics and the like for preventing contamination and growth of bacteria
  • other pharmaceutically allowable components such as a carrier, vehicle, disintegrating agent, buffer, emulsifier, suspending agent, soothing agent, stabilizer, storage agent, preservative or physiological saline
  • cells or components other than Muse cells contained in mesenchymal cells may also be contained in the cell preparation.
  • a person with ordinary skill in the art is able to add these factors and pharmaceutical agents to a cell preparation at suitable concentrations. In this manner, Muse cells can be used in the form of a pharmaceutical composition containing various types of additives.
  • the number of Muse cells contained in the cell preparation prepared in the manner described above can be suitably adjusted in consideration of the gender, age and body weight of the subject, disease state and state in which the cells are used so as to obtain the desired effect in treatment of chronic kidney disease (such as improvement of creatinine clearance, reduction of serum creatinine concentration, reduction of blood urea nitrogen, reduction of glomerulosclerosis area).
  • chronic kidney disease such as improvement of creatinine clearance, reduction of serum creatinine concentration, reduction of blood urea nitrogen, reduction of glomerulosclerosis area.
  • a mouse model of chronic kidney disease was produced by administration of doxorubicin hydrochloride, and various types of effects of transplanting Muse cells were examined. Extremely superior effects were obtained by administering SSEA3-positive cells to Balb/c mice and SCID mice weighing about 20 g to 30 g at 2 ⁇ 10 4 cells/animal.
  • the cell preparation of the present invention may be administered a plurality of times (such as 2 to 10 times) at a suitable interval (such as twice per day, once per day, twice per week, once per week, once every two weeks, once every one month, one every two months, once every six months) until the desired therapeutic effect is obtained.
  • the therapeutically effective dose is preferably administered, for example, 1 to 10 times at 1 ⁇ 10 3 cells to 1 ⁇ 10 7 cells per individual.
  • examples of total individual doses include 1 ⁇ 10 3 cells to 1 ⁇ 10 8 cells, 1 ⁇ 10 4 cells to 5 ⁇ 10 7 cells, 2 ⁇ 10 4 cells to 2 ⁇ 10 7 cells, 5 ⁇ 10 4 cells to 5 ⁇ 10 6 , and 1 ⁇ 10 5 cells to 1 ⁇ 10 6 cells.
  • the cell preparation of the present invention has a heterologous relationship with mice administered the preparation since the preparation is derived from Muse cells of human origin.
  • an immunosuppressant such as cyclosporin
  • an immunosuppressant is administered either prior or simultaneous to administration of the heterologous cells in order to suppress an immune response in the body caused by the heterologous cells.
  • the inventors of the present invention have previously found that a population of Muse cells in the form of mesenchymal cells inherently demonstrates potent immunosuppression and that Muse cells have a similar action.
  • an immunosuppressant is not required to be used in a mouse model in which an immunosuppressant is not used.
  • remarkable improvement of renal function attributable to the cell preparation of the present invention was observed without using an immunosuppressant (refer to Examples 1 to 6).
  • the cell preparation of the present invention is able to improve or restore to normal (or normal values) renal function in chronic kidney disease patients.
  • improvement of renal function refers to alleviation of various symptoms accompanying chronic kidney disease and inhibition of the progression thereof, and preferably refers to alleviation of symptoms to a degree that they do not present a problem during the course of daily life.
  • returning of renal function to normal refers to returning all symptoms attributable to chronic kidney disease to the state prior to the onset of kidney disease.
  • BUN levels decrease as renal function improves or approaches normal in the same manner as serum creatinine. Furthermore, in humans, the normal range for serum creatinine is 0.4 mg/dl to 1.2 mg/dl, while the normal range for BUN is 8 mg/dl to 20 mg/dl.
  • mice were strictly observed for the experimental protocol using mice in the present example, and experimental animals were prepared in accordance with these regulations under the supervision of the Tohoku University Experimental Animal Center. More specifically, a mouse chronic kidney disease model was prepared by administering doxorubicin hydrochloride (Sigma Corp.) into a caudal vein of Balb/c mice and SCID mice (males, age 11 to 13 weeks) at 11.5 ⁇ g/g of mouse body weight.
  • doxorubicin hydrochloride Sigma Corp.
  • SCID mice males, age 11 to 13 weeks
  • Example 1 were divided into three groups, and Muse cells (2 ⁇ 10 4 cells, 200 ⁇ l), human bone marrow-derived non-Muse cells (2 ⁇ 10 4 cells, 200 ⁇ l) or physiological saline (200 ⁇ l) were administered into a caudal vein of mice in each group one week after administration of doxorubicin hydrochloride. Subsequently, after allowing the passage of a prescribed amount of time, creatinine clearance, serum creatinine, blood urea nitrogen (BUN) and urine protein were measured in accordance with ordinary methods for each mouse followed by evaluation of the therapeutic effects of Muse cells on the chronic kidney disease mice. Furthermore, although all of the cells used for administration were of human origin, an immunosuppressant was not used throughout the experimental period when the cells were administered to the mice.
  • Serum creatinine concentrations in the Muse cell dose group were lower in comparison with the physiological saline dose group, demonstrating a statistically significant difference therewith.
  • the non-Muse cell dose group did not demonstrate a statistically significant difference when compared with the physiological saline dose group.
  • Blood urea nitrogen (BUN) concentration (mg/dl) was measured six weeks after administration of doxorubicin hydrochloride in order to investigate urine excretory function of the kidneys. As shown on the left side of FIG. 2 , blood urea nitrogen concentrations decreased in the Muse cell dose group in comparison with the non-Muse cell dose group and physiological saline dose group. Moreover, when urine protein/creatinine ratio was measured in voided urine, this ratio was lower in the Muse cell dose group in comparison with the other groups, and renal function was suggested to be improved (right side of FIG. 2 ).
  • FIG. 3 The glomerular repair effects of Muse cells on glomerular sclerosis accompanying chronic kidney disease were examined six weeks after administration of doxorubicin hydrochloride ( FIG. 3 ). Each mouse was sacrificed followed by preparing renal tissue sections and staining the sections with PAS. As a result of this staining, the degree of glomerular sclerosis was observed from changes in the glomerular basement membrane.
  • the top of FIG. 3 indicates renal tissue (glomerulus) sections of each mouse in the Muse cell, non-Muse cell and physiological saline dose groups. In the Muse cell dose group (left side), the glomerular basement membrane can be seen to be extremely well-defined.
  • the top row of images in FIG. 7 consists of GFP fluorescent images in the case of having administered Muse cells (center panel), images obtained by AQP1 staining (right panel), and images obtained by superimposing the two (left panel).
  • GFP-positive Muse cells express a molecular marker of proximal renal tubule epithelial cells in the form of aquaporin
  • the administered Muse cells were suggested to accumulate in proximal renal tubules and differentiate into proximal renal tubule cells.
  • cells not stained with primary antibody to GFP and AQP1 were used as negative controls (bottom row in FIG. 7 ).
  • Muse cells administered into a caudal vein of chronic kidney disease model mice were suggested to accumulate at sites of kidney disease and greatly contribute to reconstruction and repair of glomeruli, distal renal tubules and proximal renal tubules.
  • a study was made of the migration ability of Muse cells in vitro according to the Boyden chamber method with respect to accumulation of Muse cells at sites of kidney disease. More specifically, the BD MatrigelTM Invasion Chamber (BD Bioscience-Discovery Labware Inc.) was used for the Boyden chamber, and the chamber contained BD Falcon Cell Culture Inserts having a pore size of 8.0 ⁇ m. Matrigel Matrix was applied to the upper surface of the inserts.
  • Serum from the disease model mice was added to the lower portion of the inserts and the inserts were then inoculated with Muse cells (3.5 ⁇ 10 4 cells/well) or non-Muse cells (3.5 ⁇ 10 4 cells/well). After culturing for 20 hours, the number of cells that passed through the inserts was determined under a microscope. The results are shown in FIG. 8 . The number of cells present per field as observed with the high power field of a microscope is plotted on the vertical axis. Hardly any cells were observed to pass through the inserts in a system containing human Muse cells but not containing disease model mice serum or in a system containing non-human Muse cells but not containing disease model mice serum.
  • Muse cells demonstrated extremely high migration, and this migration was prominent in comparison with conditions consisting of non-Muse cells combined with disease model mice serum.
  • the disease model mice serum was suggested to contain some type of factor for inducing migration of Muse cells.
  • Muse cells and non-Muse cells were respectively adhered to a culture dish, and after culturing overnight, the cell nuclei thereof were stained with Hoechest 33342 stain (Sigma Corp.). Continuing, after treating the cells with trypsin, the cells were counted and 2 ⁇ 10 4 cells were administered into a caudal vein of the chronic kidney disease model mice. Renal tissue was fixed in accordance with ordinary methods 24 hours after administration and observed under a fluorescence microscope. Fluorescent images obtained following administration of Muse cells are shown in FIG. 9 , while fluorescent images obtained following administration of non-Muse cells are shown in FIG. 10 .
  • SCID chronic kidney disease mice
  • Muse cells 2 ⁇ 10 4 cells, 200 human bone marrow-derived non-Muse cells (2 ⁇ 10 4 cells, 200 ⁇ l) or physiological saline (200 ⁇ l) into a caudal vein of mice in each group one week after administration of doxorubicin hydrochloride in the same manner as Example 3.
  • creatinine clearance was measured for each mouse over time, and the results are shown in FIG. 11 .
  • the administered Muse cells were suggested to accumulate in glomeruli and differentiate into podocytes. Moreover, when the Muse cells were immunofluorescence-stained using antibody to a surface antigen marker of intravascular endothelial cells in the form of CD31, the administered Muse cells were suggested to differentiate to vascular endothelial cells in glomeruli ( FIG. 13 ). In this manner, the administered Muse cells were suggested to have the potential to accumulate at disease sites and differentiate into cells that compose renal tissue even in SCID mice of a chronic kidney disease model.

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN107050050A (zh) * 2017-04-19 2017-08-18 樊均明 一种肾小球和肾小管复合损伤的猕猴慢性肾病模型的建立方法
CN110869034A (zh) * 2017-06-20 2020-03-06 国立大学法人名古屋大学 利用多能干细胞进行的伴随胎儿生长迟缓的脑损伤的改善和治疗
US20220387507A1 (en) * 2019-10-31 2022-12-08 Life Science Institute, Inc. Therapy for interstitial cystitis by pluripotent stem cells
EP4061400A4 (en) * 2019-11-20 2024-01-10 Cornell University Generation of kidney glomerular specific endothelial cells and methods of use

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JP7618191B2 (ja) * 2016-07-01 2025-01-21 国立大学法人東北大学 臓器線維症の予防または治療剤
JP7072777B2 (ja) * 2018-07-03 2022-05-23 株式会社生命科学インスティテュート 慢性腎障害治療のための多能性幹細胞

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US20110070647A1 (en) * 2009-07-15 2011-03-24 Mari Dezawa Pluripotent stem cell that can be isolated from body tissue

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WO2003013588A1 (en) * 2001-08-08 2003-02-20 Kaken Pharmaceutical Co., Ltd. Kidney regeneration material comprising cells and cell growth factor
CA2521217C (en) * 2003-04-01 2013-05-14 United States Of America Department Of Veteran's Affairs Stem-cell, precursor cell, or target cell-based treatment of multi-organ failure and renal dysfunction
JP5598864B2 (ja) * 2011-12-05 2014-10-01 北海道公立大学法人 札幌医科大学 細胞増殖方法ならびに組織の修復および再生のための医薬
WO2014027474A1 (ja) * 2012-08-17 2014-02-20 株式会社Ｃｌｉｏ 心筋梗塞の修復再生を誘導する多能性幹細胞

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US20110070647A1 (en) * 2009-07-15 2011-03-24 Mari Dezawa Pluripotent stem cell that can be isolated from body tissue

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107050050A (zh) * 2017-04-19 2017-08-18 樊均明 一种肾小球和肾小管复合损伤的猕猴慢性肾病模型的建立方法
CN110869034A (zh) * 2017-06-20 2020-03-06 国立大学法人名古屋大学 利用多能干细胞进行的伴随胎儿生长迟缓的脑损伤的改善和治疗
EP3643317A4 (en) * 2017-06-20 2021-03-03 National University Corporation Nagoya University IMPROVEMENT AND TREATMENT OF BRAIN DISORDERS RESULTING FROM FETAL GROWTH DELAY USING PLURIPOTENT STEM CELLS
US20220387507A1 (en) * 2019-10-31 2022-12-08 Life Science Institute, Inc. Therapy for interstitial cystitis by pluripotent stem cells
US12491211B2 (en) * 2019-10-31 2025-12-09 Tohoku University Therapy for interstitial cystitis by pluripotent stem cells
EP4061400A4 (en) * 2019-11-20 2024-01-10 Cornell University Generation of kidney glomerular specific endothelial cells and methods of use

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