WO2021169017A1 - Utilisation de cellules souches mésenchymateuses dans le traitement de la pneumonie à covid-19 sévère - Google Patents

Utilisation de cellules souches mésenchymateuses dans le traitement de la pneumonie à covid-19 sévère Download PDF

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WO2021169017A1
WO2021169017A1 PCT/CN2020/086653 CN2020086653W WO2021169017A1 WO 2021169017 A1 WO2021169017 A1 WO 2021169017A1 CN 2020086653 W CN2020086653 W CN 2020086653W WO 2021169017 A1 WO2021169017 A1 WO 2021169017A1
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stem cells
mesenchymal stem
ace2
cells
viral pneumonia
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PCT/CN2020/086653
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Chinese (zh)
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赵春华
冷子宽
杜东书
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上海大学
郑州大学第一附属医院
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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
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues

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  • the present disclosure belongs to the field of biomedical technology, and relates to a method for treating severe or critical COVID19 pneumonia by using ACE2-negative mesenchymal stem cells.
  • ACE2 is a type I glycoprotein on the cell membrane. It has two major functional domains, namely the extracellular and transmembrane domains containing carboxypeptidase functions. Although ACE2 and ACE1 share 61% homology, their physiological function is to remove the C-terminal amino acid residues of angiotensin II (AngII) to become inactive angiotensin 1. Because the renin-angiotensin system (RAS) is related to blood pressure regulation, there are many studies in cardiovascular diseases. It has been found that ACE2 gene polypeptide is associated with hypertension, left ventricular hypertrophy, and atrial fibrillation.
  • AngII angiotensin II
  • RAS renin-angiotensin system
  • Viruses are completely parasitic organisms and must enter the host cell through the receptor to survive and multiply.
  • SARS virus receptor the research work of many research groups around the world has confirmed that the first step for 2019-nCoV to invade host cells is to specifically bind to the ACE2 receptor on the human cell surface through the virus surface spike.
  • ACE2 receptors such as type II lung epithelial cells and small intestinal epithelium.
  • 2019-nCoV invades the cells of the corresponding part, it will cause the corresponding organ dysfunction and even failure.
  • the most important damaged organ is the lung.
  • 2019-nCoV The sense single-stranded RNA virus 2019-nCoV is transmitted from certain animals or patients to humans through droplets and close contact.
  • 2019-nCoV uses ACE2 on type II lung epithelial cells as the receptor, and the viral spike protein binds to it, and the virus is endocytosed into the cell. With the help of cathepsin in the lysosome, the protein coat of the virus is digested. 2019-nCoV "hijacks" the host cell's protein translation system.
  • direct translation includes the proteins required by the virus to replicate genome enzymes and structures such as envelopes and spines, and then assemble them into new virus particles.
  • a replication (life) cycle of the virus (6 steps: enter the human body to adhere, penetrate the membrane, unshell, replicate, assemble, and release).
  • a large number of viruses destroy epithelial cells and release viruses, thereby infecting more cells. Damaged epithelial cells can release contents, causing acute inflammation such as inflammatory cell extravasation, and severe cases can cause cytokine release syndrome. It then leads to acute lung injury and damage to various organs in the body, causing multiple organ failure, which seriously threatens people's lives.
  • the new coronavirus disease (COVID-19) caused by the coronavirus 2019-nCoV has had a huge negative social impact and poses a huge threat to global public health.
  • the severity of COVID-19 pneumonia can be divided into four levels: light, normal, severe, and critical.
  • cytokine storms cause severe acute respiratory syndrome and many other serious complications. Preventing and reversing the cytokine storm may be the key to rescuing critically ill patients.
  • MSCs Mesenchymal stem cells
  • a mesenchymal stem cell is provided.
  • an ACE2-negative mesenchymal stem cell is provided.
  • a negative ACE2 (ACE2 also as -) refers to the use of the prior art known means for detecting ACE2 in mesenchymal stem cells or cell surface without detectable levels of ACE2.
  • the mesenchymal stem cells are derived from: fat, umbilical cord blood, umbilical cord, bone marrow, placenta. In other embodiments, the mesenchymal stem cells are autologous mesenchymal stem cells, or allogeneic mesenchymal stem cells.
  • ACE2-negative mesenchymal stem cells are obtained through the following culture conditions:
  • a temperature of 30°C to 40°C such as 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40°C, and the range between any two values (may not be an integer value);
  • 4% to 6% CO 2 e.g. 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0%
  • mesenchymal stem cells are cultured in DMEM/F12 medium for 2 to 20 generations (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10).
  • the DMEM/F12 medium is supplemented with any one or a combination selected from the following:
  • w/v 0.1% to 30% w/v, such as 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25% w/v FBS,
  • 1% to 3% w/v such as 1, 1.5, 2, 2.5, 3% w/v antibiotics (e.g. penicillin/streptomycin), and
  • 0.1 mM to 30 mM such as 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 mM GlutaMAX TM -I.
  • the use of the aforementioned ACE2-negative mesenchymal stem cells for the treatment of viral pneumonia is also provided.
  • the use of the aforementioned ACE2-negative mesenchymal stem cells in the preparation of drugs for the treatment of viral pneumonia is also provided.
  • the ACE2-negative mesenchymal stem cells of the present application are particularly effective against severe viral pneumonia.
  • the virus is selected from: rhinovirus, coronavirus, adenovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, Echo virus, Coxsackie virus.
  • the coronavirus is selected from: SARS-CoV, MERS-CoV, and 2019-nCoV.
  • a method for treating viral pneumonia including the steps of: administering a therapeutically effective amount of ACE2-negative mesenchymal stem cells to the patient.
  • the patient refers to a virus carrier, especially a patient who has or may have symptoms due to the presence of the virus.
  • a virus carrier especially a patient who has or may have symptoms due to the presence of the virus.
  • patients are especially severe or critically ill patients.
  • the virus is selected from: rhinovirus, coronavirus (may mention SARS-CoV, MERS-CoV, 2019-nCoV), adenovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, Echo virus, Coxsackie Virus.
  • the mesenchymal stem cells are selected from: adipose mesenchymal stem cells, cord blood mesenchymal stem cells, umbilical cord mesenchymal stem cells, bone marrow mesenchymal stem cells, placental mesenchymal stem cells.
  • the mesenchymal stem cells are autologous mesenchymal stem cells, or allogeneic mesenchymal stem cells.
  • therapeutically effective amount refers to the amount of the drug, compound, or pharmaceutical composition necessary to obtain any one or more beneficial or desired therapeutic results .
  • beneficial or desired results include: improving clinical results (eg, reducing morbidity, mortality, improving one or more symptoms), reducing the severity, delaying the onset of the disease (including the disease or its complications, in the development process of the disease) Intermediate pathological phenotypes, biochemical, histological and/or behavioral symptoms presented in ).
  • Figure 1 CT image of a severely ill patient with COVID-19 (cell transplantation performed on January 31).
  • Figure 2A to Figure 2C Mass spectrometry flow cytometry of peripheral blood mononuclear cells in critically ill patients.
  • Figure 3A to Figure 3N RNA sequence analysis.
  • ACE2 (Figure 3A), TMPRSS2 (Figure 3B), TGF- ⁇ (Figure 3C), HGF (Figure 3D), LIF (Figure 3E), GAL (Figure 3F), NOA1 (Figure 3G), FGF (Figure 3H), VEGF (Figure 3I), EGF (Figure 3J), BDNF (Figure 3K), NGF ( Figure 3L), SPA ( Figure 3M) and SPC ( Figure 3N).
  • a dot represents a cell, and dark and light colors represent high expression and low expression, respectively.
  • Figure 4A to Figure 4F Using flow cytometry to identify the expression of MSCs cell surface markers.
  • Figures 5A and 5B high-throughput single-cell sequencing of cell gene numbers (Figure 5A) and characteristic maps of UMIs ( Figure 5B).
  • FIG. 6A to Figure 6D 10 ⁇ -scRNA sequence analysis MSCs marker gene expression: CD105 ( Figure 6A), CD90 ( Figure 6B), CD73 ( Figure 6C) and CD45 ( Figure 6D).
  • FIG. 7A and Figure 7B ACE2 gene is not expressed in MSCs (Figure 7A); only one ACE2 + MSC and the remaining 12499 ACE2 - MSCs are differentially expressed in the first 60 genes ( Figure 7B).
  • Figure 8A and Figure 8B TMPRSS2 gene expression (Figure 8A); and differentially expressed genes between TMPRSS2 + MSC and TMPRSS2 - MSC ( Figure 8B).
  • Figures 9A to 9C High-throughput single-cell sequencing technology revealed that MSCs highly expressed genes differentiated in the endoderm direction (Figure 9A), and highly expressed SPA (Figure 9B) and SPC (Figure 9C).
  • Figure 10A to Figure 10D Serum cytokine IL-10 (Figure 10A), growth factor VEGF ( Figure 10B), chemokine IP-10 (Figure 10C) and tumor necrosis factor TNF- ⁇ ( Figure 10D) before and after MSCs treatment Proportion.
  • Figures 11A to 11C Flow cytometry results of peripheral blood mononuclear cells.
  • RNA real-time reverse transcription polymerase chain reaction RT-PCR
  • the RT-PCR test is carried out at the Chinese Center for Disease Control and Prevention.
  • the sequence used to target the membrane gene of the coronavirus (Lancet, 2020Feb 15,395-10223: 497-506) is as follows:
  • the expansion conditions are: 50°C for 15 minutes, 95°C for 3 minutes, 45 cycles, each cycle includes 95°C for 15 seconds and 60°C for 30 seconds.
  • the oxygen saturation is ⁇ 93%
  • ICU monitoring and treatment is required.
  • DMEM/F12 fetal bovine serum (FBS), transglutaminase-I, trypsin, penicillin and streptomycin were all purchased from Gibco (California, USA). All other reagents are of analytical grade and do not require further purification.
  • the adipose-derived mesenchymal stem cells were cultured in DMEM/F12 medium (supplemented with 10% FBS, 1% penicillin/streptomycin and 2mM GlutaMAX TM -I) under 4% to 6% CO 2 at 30 to 40°C for 2 generations To the 10th generation.
  • the surface phenotypes CD29, CD44, CD105, CD73, and CD90 were positive by flow cytometry; CD31, CD34, and CD45.
  • the sequencing library is constructed.
  • the library was constructed using a chromium controller (10x Genomics, Pleasanton, California).
  • GemCode technology is used to encapsulate single cells containing barcode oligonucleotides, reagents and gel beads into nanoliter GEMs (latex gel beads).
  • GEMs latex gel beads
  • single cell polyadenylation mRNA cleavage and barcode reverse transcription are performed. Clean up the GEMs after RT and amplify cDNA. Fragment the cDNA, repair the ends of the fragments, and add A-tailing to the 3'end.
  • the adapter Connect the adapter to the segment with the double-sided SPRI selected. After sample exponential PCR, another two-way SPRI selection is performed. The quality control library was sorted. The final library is quantified in two ways: using the Agilent 2100 bioanalyzer to determine the average molecular length, and using real-time quantitative PCR to quantify the library.
  • the inventors performed high-throughput single-cell RNA sequencing (10 ⁇ RNA-seq) to accurately detect the full gene expression profile of MSCs, especially the ACE2 and TMPRSS2 genes, as well as the secretion factors, nutritional factors, and alveolar epithelial cells II ( AT-2) Genes related to differentiation.
  • MSCs were suspended in 100ml of normal saline, and the total number of transplanted cells was calculated at 1 ⁇ 10 6 cells per kilogram of body weight.
  • the window period of cell transplantation refers to the time during which the symptoms or/and signs are still getting worse while the expected treatment is being performed. The injection takes about 40 minutes and the speed is about 40 drops per minute.
  • -Secondary efficacy indicators mainly include: total lymphocyte count and subpopulations, chest CT, respiratory rate and patient symptoms (especially fever and shortness of breath);
  • the treatment measures ie antiviral drugs and respiratory support
  • results are also recorded.
  • PBMC samples were collected from COVID-19 patients who received MSCs transplantation, and PBMC from healthy donors were used as a control group.
  • CD45 antibodies Three samples from healthy donors, patients at the beginning, and patients on the 6th day after treatment were stained with CD45 antibodies. These antibodies were labeled with different metal tags (such as 89, 141, and 172) to minimize the number of samples. Internal cross-reactions between.
  • the antibody was combined with MaxPar ⁇ 8 polymer kit (Fluidigm). All metal-bound antibodies are titrated to the optimal concentration before use.
  • the cells were counted, diluted to 1 ⁇ 10 6 cells/ml in PBS, and permeated with 80% methanol at 0°C for 15 min. Washed 3 times in CSB, incubated with 50 ⁇ L CSD antibody at RT for 30 min, washed three times in CSB, and incubated overnight in fix-perm buffer (Fluidigm) with 0.125 ⁇ m intercalant at 4°C.
  • the cells were intercalated and cultured, they were washed 3 times with frozen PBS and 3 times with deionized water. Before collection, the sample was resuspended in deionized water containing 10% EQ 4 element beads (Fluidigm), and the cell concentration was adjusted to 1 ⁇ 10 6 cells/ml. Data collection was performed on a Helios mass cytometer (Fluidigm). The original FCS data was normalized, and everyone’s .fcs files were collected.
  • the inventors performed MSCs transplantation experiments on 7 COVID-19 patients from Beijing You'an Hospital to explore the safety and effectiveness of the cell therapy.
  • the inventor also performed MSCs vein transplantation on patients. Observe for 14 days after cell injection.
  • the main safety consideration is toxic effects, including infusion or allergic reactions.
  • the main therapeutic effect is the immunomodulatory function of the infused mesenchymal stem cells, combined with plasma C-reactive protein levels and blood oxygen saturation.
  • the secondary efficacy indicators mainly include the total number and subpopulations of lymphocytes determined by mass spectrometry flow cytometry, chest CT, respiratory rate, and patient symptoms (especially fever and shortness of breath).
  • the clinical manifestations such as fever and shortness of breath generally alleviate or disappear within 2 to 4 days, and the blood oxygen saturation can reach more than 95%; laboratory examination indicators C-reactive protein can be significantly reduced within 7-10 days, chest CT shows ground glass-like changes in the lungs, which are significantly relieved in about 7 days (Figure 1); peripheral blood immune cell subsets can be reversed to pre-infection levels (Figure 2A to Figure 2C) ).

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Abstract

L'invention concerne l'utilisation de cellules souches mésenchymateuses dans le traitement de la pneumonie à COVID-19 sévère. L'invention concerne des MSC ACE2 négatives, et se caractérise en ce qu'elle est sûre et efficace pour administrer les MSC à un patient souffrant de COVID-19, en particulier un patient gravement atteint, par injection intraveineuse. Les MSC ACE2 négatives peuvent jouer un rôle positif grâce à des effets immunomodulateurs directs sur une tempête de cytokines et des cellules immunitaires, protégeant ainsi les fonctions du foie et les fonctions myocardiques.
PCT/CN2020/086653 2020-02-25 2020-04-24 Utilisation de cellules souches mésenchymateuses dans le traitement de la pneumonie à covid-19 sévère WO2021169017A1 (fr)

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US20210308190A1 (en) * 2020-04-07 2021-10-07 Miguelangelo J. Perez-Cruet Human umbilical cord blood mesenchymal stem cell transfusion immunotherapy for treatment of cytokine storm associated with coronavirus infection
WO2023063739A1 (fr) * 2021-10-14 2023-04-20 재단법인대구경북과학기술원 Vésicules extracellulaires dérivées de cellules souches mésenchymateuses et auxquelles l'ace2 est fixée, et leur utilisation
WO2024041292A1 (fr) * 2022-08-22 2024-02-29 中国药科大学 Utilisation de cellules souches mésenchymateuses de cordon ombilical dans la prévention de maladies pulmonaires provoquées par une infection virale

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US20210308190A1 (en) * 2020-04-07 2021-10-07 Miguelangelo J. Perez-Cruet Human umbilical cord blood mesenchymal stem cell transfusion immunotherapy for treatment of cytokine storm associated with coronavirus infection
WO2023063739A1 (fr) * 2021-10-14 2023-04-20 재단법인대구경북과학기술원 Vésicules extracellulaires dérivées de cellules souches mésenchymateuses et auxquelles l'ace2 est fixée, et leur utilisation
WO2024041292A1 (fr) * 2022-08-22 2024-02-29 中国药科大学 Utilisation de cellules souches mésenchymateuses de cordon ombilical dans la prévention de maladies pulmonaires provoquées par une infection virale

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