WO2021231652A1 - Utilisation du plasmide p62 pour traiter ou réduire la gravité d'infections à coronavirus - Google Patents

Utilisation du plasmide p62 pour traiter ou réduire la gravité d'infections à coronavirus Download PDF

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Publication number
WO2021231652A1
WO2021231652A1 PCT/US2021/032093 US2021032093W WO2021231652A1 WO 2021231652 A1 WO2021231652 A1 WO 2021231652A1 US 2021032093 W US2021032093 W US 2021032093W WO 2021231652 A1 WO2021231652 A1 WO 2021231652A1
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WIPO (PCT)
Prior art keywords
plasmid
disease
patient
inflammatory
agent
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PCT/US2021/032093
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English (en)
Inventor
Alexander SHNEIDER
Vladimir Gabai
Franco Venanzi
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Curelab Oncology, Inc.
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Publication of WO2021231652A1 publication Critical patent/WO2021231652A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • inflammatory diseases include, but are not limited to osteoporosis, obesity, metabolic syndrome, type 2 diabetes, fat liver, inflammatory bowel disease, chronic pancreatitis, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), osteoarthritis, multiple sclerosis (MS), psoriasis, congestive heart failure (CHF), atherosclerosis, neurodegenerative diseases (ALS, Parkinson, Alzheimer’s, Huntington disease), asbestosis and silicosis.
  • the disclosure includes using p62 plasmid to prevent the development of disease symptoms in patients infected with a coronavirus, reduce the severity of symptoms in patients infected with coronavirus, reduce the duration of disease in such patients, and/or reduce the negative effect of a coronavirus infection on patients’ health after the active phase of the infection is over.
  • p62 plasmid can be administered via standard routes of administration or by utilizing alternative routes. By limiting chronic inflammation, Mariagen will not reduce a person’s chance of getting infected but would make the resulting infection a rather trivial discomfort.
  • p62 may be delivered as a viral vector, RNA and or a protein. Also, p62 can be administered via a microorganism containing a DNA encoding the p62 with the vector been expressed in the microorganism or in a cell of the human or animal which have received the p62-encoding gene from the microorganism.
  • Coronaviruses constitute a broad class of RNA viruses infecting animals and humans. Coronavirus infections constitute a major public health challenge.
  • SARS-CoV coronavirus strain
  • MERS-CoV strain resulted in the Middle East respiratory syndrome (MERS), also known as “camel flu”, with an almost 35% death rate.
  • MERS Middle East respiratory syndrome
  • the current global pandemic of COVID- 19 strain began at the end of 2019 in China and spread globally within less than 4 months. This pandemic has no analogs in modern history in its devastating effect on the global economy and societal changes it is causing.
  • COVID-19 chronic inflammation, such as cytokine storm, for which we propose here a novel solution.
  • Every condition which causes patients to be in a high-risk group (age of 65+, type 2 diabetes (T2D), metabolic syndrome, etc.) is a disease of chronic inflammation.
  • T2D type 2 diabetes
  • T2D type 2 diabetes
  • COVID-19 progresses to hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), both of which are mediated by widespread inflammation and a dysregulated immune response.
  • ARDS acute respiratory distress syndrome
  • MSCs Mesenchymal stem cells
  • MSCs multipotent stromal cells that mediate immunomodulation and regeneration, could be of potential benefit to a subset of COVID-19 subjects with acute respiratory failure and syndromes taking place post COVID and/or other coronavirus infections.
  • a vector encoding p62 and/or p62 protein changes MSC making them to reduce production of pro-inflammatory cytokines and chemokines, increase production of anti-inflammatory cytokines and chemokines, and/or differentiate forming cells which are necessary for the damaged organ to regain its normal functionality.
  • the effect may be indirect.
  • local cells at the site of p62 application or remote cells acquiring administered p62 may generate (via secretion of some molecules) signals to cells in the same or a remote organ, which make these receiving cells to act in an anti-inflammatory, therapeutic or a regenerative fashion.
  • FIG. 1 Cytokines and chemokines release was analyzed in medium from bone marrow mesenchymal stem cell cultures obtained from the different experimental groups.
  • A BM-MSC pc3.1 plasmid vector transfected.
  • B BM-MSC p62 DNA plasmid transfected.
  • C BM-MSCs cultured 24h with conditional medium harvested from pc3.1 plasmid vector transfected cells, washed and cultured for 2d with fresh culture medium (cytokines/chemokines secretion was evaluated on fresh medium after 2d of culture).
  • post-COVID syndrome The incidence of post-COVID syndrome is estimated at 10-35%, while for hospitalized patients it may reach 85%. More than one third of patients with post-COVID syndrome have pre-existing comorbidities, hypertension and diabetes mellitus being the most common. Adverse outcomes were not localized; rather, they affected different human systems, including:
  • immune system e.g., Guillain-Barre syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease
  • hematological system vascular hemostasis, blood coagulation
  • pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis),
  • cardiovascular system myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy
  • a segment of a protein may be used, for example a p62 with some domains deleted and/or altered.
  • a p62 can be of a human origin or from another organism, so the sequence of the administered p62 can be identical or different to the sequence of the organism where it is administered.
  • a p62 (protein or p62-encoding nucleic acid) can be administered in a pharmaceutical formulation and/or via a regimen containing a delivery system (including but not limited to polymers, proteins, lipids, solvents, surfactants, nucleic acids, microorganisms, electroporation), factors influencing extracellular matrix, factors influencing uptake by the cells, factors influencing trafficking to the organ of interest such as damaged organ or an immune organ or molecules and/or treatments where p62 can have an additive effect with or synergize with other treatments including but not limited to treatments and factors modulating blood vessels and capillary state, immune system modulators, modulators of a respiratory activity, modulators of an inflammation, over the counter drugs, prescription drugs, medical treatments.
  • a delivery system including but not limited to polymers, proteins, lipids, solvents, surfactants, nucleic acids, microorganisms, electroporation
  • factors influencing extracellular matrix including but not limited to polymers, proteins, lipids, solvents, surfactants,
  • a p62 can be administered together with a drug such as an inhibitor of RNA-dependent-RNA polymerase, an inhibitor of a cellular protease, an anti-malaria agent, an anti-infective agent, an immune modulator, an anti-inflammatory drug, an antioxidant, an agent reducing high fever, a chemotherapeutic agent, or an agent assisting beading in case of a partial or full lung dysfunction Codon optimization and techniques modulating p62 expression, composition, post-translational modification or splicing of p62 are also included under the term of p62 for prevention and/or treatment of COVID and/or coronavirus infections.
  • a treated patients may be humans or animals including pets.
  • a patient who is currently ill (virus positive) or was ill in the past, or may become ill should be administered p62 formulation to reduce, revert or preclude coronavirus post-disease syndrome.
  • Full length cDNA encoding the longer isoform of p62 Transcript Variant 1, GenBank reference No.
  • NP 003891 was amplified by PCR (HotStar HiFidelity Polymerase Kit Qiagen) using the following primers: FW : 5-CCCGCTAGCATGGCGTCGCTCACCGTG-3 and REV: 5’- CCCAAGCTTTC ACAACGGCGGGGGATGCTTTG-3 ’ .
  • PCR products were purified and Nhe I - Hind III digested fragments cloned into a DNA vector with nucleic acid sequence corresponding to pcDNA3.1 resulting in p62 plasmid. The DNA constructs were confirmed by sequencing.
  • FVB/N females were anesthetized and, after exposure of the femoral quadriceps, injected with 100 pg DNA (1 mg/mL) in saline using an insulin syringe. Mice were injected two times (at 4 and 2 weeks before OVX). 100% of mice ovariectomized both not injected and injected with empty plasmid vector (negative control), developed osteoporosis by day 60 after OVX. In contrast, OVX mice injected with p62 plasmid showed inhibition of the induced osteoporosis.
  • P62 plasmid can alleviate diet-induced obesity and metabolic dysfunctions
  • HCD high-calorie diet
  • DIO diet- induced obesity
  • HCD-induced obesity Due to this anti-inflammatory response, we further tested whether the plasmid can alleviate HCD-induced obesity and associated metabolic and feeding impairments. Indeed, p62 plasmid significantly reversed effects of HCD on the body mass index (BMI), levels of glucose, insulin and glycosylated hemoglobin (HbAlc). Furthermore, p62 plasmid partially restored levels of the satiety hormone, serotonin, and tryptophan, simultaneously reducing activity of monoamine oxidase (MAO) in the brain affected by the HCD. Finally, the plasmid partially reversed increased food consumption caused by HCD. Therefore, the administering of p62 plasmid alleviates both metabolic and behavioral components of HCD-induced obesity.
  • BMI body mass index
  • HbAlc glycosylated hemoglobin
  • MAO monoamine oxidase
  • a human patient with a disease comprising chronic inflammation for example, metabolic syndrome as in the Example 3, diabetes, hypertension, psoriasis, a mental disorder, a central nervous system (CNS) disorder, osteoporosis (as in example 2), inflammatory bowel disease (IBD), colitis, Crohn's disease, a rheumatoid disorder, arthritis, or another disease associated with pro-inflammatory cytokines) tested positive for coronavirus and/or having mild symptoms is administered p62 plasmid.
  • a dose of ranging from 1 to 5 mg is administered orally once a week.
  • the patient receives p62 plasmid until full recovery determined, for example, as the elimination of viral RNA from the patient’s laboratory samples.
  • the patient does not develop severe coronavirus symptoms, such as breathing problems, shortness of breath, or necessity of hospitalization, to the extent possible for an untreated patient.
  • a human patient infected with coronavirus with or without comorbidities has a high level of pro-inflammatory cytokines, for example, more than 50% of a level typical for young healthy adults.
  • the determination of the levels of pro-inflammatory cytokines is performed using enzyme-linked immunosorbent assays (ELISAs).
  • ELISAs enzyme-linked immunosorbent assays
  • the patient is administeredp62 plasmid.
  • a dose of p62 plasmid ranging from 1 to 5 mg is administered i.m. once a week.
  • the patient receives p62 plasmid until full recovery determined, for example, as the elimination of viral RNA from the patient’s laboratory samples.
  • the patient does not develop severe symptoms with coughing and shortage of breath remaining at tolerable levels, and no or limited gastrointestinal disorders compared to a typical infected counterpart receiving no p62 plasmid.
  • a human patient tested positive for coronavirus has developed severe disease symptoms, for example, severe respiratory symptoms, shortness of breath, coughing, high fever, gastrointestinal symptoms, and/or diarrhea.
  • the patient is administered p62 plasmid to ameliorate the symptoms and the disease.
  • p62 plasmid ranging from 1 to 5 mg is administered i.m. once a day before bedtime.
  • the patient receives p62 plasmid until full recovery determined, for example, as the elimination of viral RNA from the patient’s laboratory samples. In the course of the treatment, the symptoms are reduced.
  • a group of human patients tested positive for a coronavirus are administered an antiviral agent (for example, hydroxychloroquine, chloroquine, azithromycin, an inhibitor of RNA-dependent RNA polymerase, or an inhibitor of cellular protease) in combination with p62 plasmid, which results in a lower death rate and hospitalization rate, less severe breathing problems and faster recovery than normally expected without melatonin.
  • an antiviral agent for example, hydroxychloroquine, chloroquine, azithromycin, an inhibitor of RNA-dependent RNA polymerase, or an inhibitor of cellular protease
  • a group of human patients tested positive for a coronavirus is administered an anti-inflammatory agent (for example, aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, antibodies against pro-inflammatory antibodies, and in combination with p62 plasmid, which results in a lower death rate and hospitalization rate, less severe breathing problems and faster recovery than normally expected without p62 plasmid.
  • an anti-inflammatory agent for example, aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, antibodies against pro-inflammatory antibodies, and in combination with p62 plasmid, which results in a lower death rate and hospitalization rate, less severe breathing problems and faster recovery than normally expected without p62 plasmid.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
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  • Marine Sciences & Fisheries (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé d'utilisation du plasmide p62, du vecteur non plasmidique p62, de l'ARN p62 ou de la protéine p62 pour prévenir ou réduire la gravité d'un ou de plusieurs symptômes d'une infection à coronavirus, pour réduire la durée nécessaire jusqu'à un rétablissement partiel ou complet et/ou pour empêcher le décès ou les complications faisant suite à la maladie provoquée par une infection à coronavirus chez l'homme ou l'animal.
PCT/US2021/032093 2020-05-14 2021-05-12 Utilisation du plasmide p62 pour traiter ou réduire la gravité d'infections à coronavirus WO2021231652A1 (fr)

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US63/025,160 2020-05-14

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038556A2 (fr) * 1995-06-01 1996-12-05 Rhone-Poulenc Rorer S.A. Deltap62, ses variants, sequences d'acides nucleiques les codant, et leurs utilisations en therapie genique anti-cancereuse
WO2015100446A1 (fr) * 2013-12-29 2015-07-02 Curelab Oncology, Inc. Méthodes et compositions relatives à p62/sqstm1 pour traiter et prévenir les maladies associées à une inflammation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038556A2 (fr) * 1995-06-01 1996-12-05 Rhone-Poulenc Rorer S.A. Deltap62, ses variants, sequences d'acides nucleiques les codant, et leurs utilisations en therapie genique anti-cancereuse
WO2015100446A1 (fr) * 2013-12-29 2015-07-02 Curelab Oncology, Inc. Méthodes et compositions relatives à p62/sqstm1 pour traiter et prévenir les maladies associées à une inflammation
US20190153056A1 (en) * 2013-12-29 2019-05-23 Curelab Oncology, Inc. Methods and compositions relating to p62/SQSTM1 for the treatment and prevention of inflammation-associated diseases

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