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WO2025199076A1 - Procédés d'amélioration de la fonction de greffon cardiaque - Google Patents

Procédés d'amélioration de la fonction de greffon cardiaque

Info

Publication number
WO2025199076A1
WO2025199076A1 PCT/US2025/020328 US2025020328W WO2025199076A1 WO 2025199076 A1 WO2025199076 A1 WO 2025199076A1 US 2025020328 W US2025020328 W US 2025020328W WO 2025199076 A1 WO2025199076 A1 WO 2025199076A1
Authority
WO
WIPO (PCT)
Prior art keywords
graft
mitochondria
composition
cardiac
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/020328
Other languages
English (en)
Inventor
Phillip C. Yang
Gentaro IKEDA
Yasuhiro Shudo
Koji KAWAGO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leland Stanford Junior University
Original Assignee
Leland Stanford Junior University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Leland Stanford Junior University filed Critical Leland Stanford Junior University
Publication of WO2025199076A1 publication Critical patent/WO2025199076A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K35/34—Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes
    • 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
    • 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

Definitions

  • DCD grafts provide a much needed alternative source of cardiac grafts to meet the existing need, but the longer ischemic time experienced by DCD grafts contributes to ischemia-reperfusion injury and significantly decreases myocardial function and post-transplant graft function.
  • the present invention addresses the need for improved methods of reducing ischemia-reperfusion injury in grafts.
  • the present disclosure provides methods for reducing ischemia-reperfusion injury and enhancing the function of cardiac grafts by administering mitochondria-rich extracellular vesicles to the grafts ex vivo.
  • Clinical application of the methods described here is expected to improve the prognosis of cardiac transplant patients, including those receiving DCD donor hearts, by enhancing the function and engraftment rate of the donor heart.
  • a method of reducing ischemia-reperfusion injury in a cardiac graft comprising administering to the graft ex vivo a composition comprising mitochondria-rich extracellular vesicles.
  • a method for improving the function of a cardiac graft comprising administering to the graft ex vivo a composition comprising mitochondria-rich extracellular vesicles.
  • compositions comprising mitochondria-rich extracellular vesicles for use in a method of reducing ischemia-reperfusion injury in a cardiac graft by a method including ex vivo administration of the composition to the graft.
  • a composition comprising mitochondria-rich extracellular vesicles for use in a method of improving the function of a cardiac graft by a method including ex vivo administration of the composition to the graft.
  • the method may also include where the composition is administered to the graft within at least about 1 to 2 hours prior to transplantation of the graft into a recipient.
  • the method may also include where the graft has been subjected to ischemic conditions ex vivo prior to administration of the composition.
  • the method may also include where the ischemic conditions comprise storage in an aqueous buffer for a period of time.
  • the method may also include where the period of time is from about 3-20 hours, about 3-5 hours, about 3-10 hours, about 10-20 hours, or about 12-18 hours.
  • the method may also include where the composition is administered to the graft parenterally.
  • the method may also include where the composition is administered via intramyocardial, intracoronary, intravenous, intra-arteriole, or intraventricular injection.
  • the method may also include where the vesicles express one or both of connexin 43 and endothelial marker CD31.
  • the method may also include wherein the vesicles comprise functional mitochondria.
  • FIG. 1A is a schematic representation of an in vitro experiment testing whether human mitochondria rich extracellular vesicles (MEVs) could successfully deliver intact functional human mitochondria to rat cardiac tissue which had been removed from the donor animal and stored in vitro in University of Wisconsin (UW) solution for 17 hours at 4 °C.
  • MEVs human mitochondria rich extracellular vesicles
  • FIG. IB is a bar graph showing dose-dependent expression of human mitochondrial genes in rat heart tissue following injection of either 10 8 or 10 10 MEVs into the coronary artery of hearts ex vivo.
  • FIG. 2A is a schematic representation of an in vitro experiment testing whether MEVs could improve cardiac graft health and function following transplantation where the MEVs are injected into the cardiac tissue following its removal from a donor animal and storage in vitro in University of Wisconsin (UW) solution for 17 hours at 4 °C.
  • UW University of Wisconsin
  • FIG. 2B is a bar graph showing ATP levels (ng/ml) in untreated control and MEV treated cardiac grafts 3 hours after transplantation.
  • FIG. 2C is a bar graph showing troponin-I levels (ng/ml) of recipient rats that received untreated control or MEV treated cardiac grafts. The time point is 3 hours after transplantation.
  • FIG. 3 shows representative transmission electron microscopy images of mitochondria in cardiomyocytes. Panel A shows normal structure 30 minutes after procurement. Panels B and C show severe mitochondrial swelling in both MEV-treated (C) and untreated (B) control hearts preserved in University of Wisconsin (UW) solution for 18 hours at 4 °C. Panel D shows further structural changes in the mitochondria untreated (D) control hearts 3 hours after transplantation. Panel E shows that the structural changes were attenuated in MEV-treated hearts.
  • FIG. 4A shows representative manganese-enhanced MRI (MEMRI) images acquired 7 days after transplantation
  • FIG. 4B is a bar graph showing T1 CNR (left bar in each pair) and T2 CNR (right bar in each pair) for positive control hearts (PC), mitochondrial EV-treated hearts (MEV), and untreated hearts (Control).
  • FIG. 5A shows representative Tunel staining images acquired 3 hours after transplantation with donor heart preserved for 18 hours and Tunel positive Ratio. Representative Tunel staining image of control (left panel) and MEV group (right panel). TUNEL-positive cells indicate cell death.
  • FIG. 5B is a bar graph showing average Tunel positive cell rate (Tunel & DAPI double positive/DAPI positive) in a randomly selected 6 fields of view from the middle layer of myocardium at the papillary muscle level was significantly lower in the MEV treatment group (p ⁇ 0.05), suggesting a protective effect of MEV treatment. Values are means ⁇ SD, *P ⁇ .05
  • mitochondrial transplantation therapy in the form of mitochondria-rich extracellular vesicles administered to the graft can be used to reduce ischemia-reperfusion injury and enhance function of cardiac grafts, including grafts that have been subjected to a period of ischemia, for example by storage in an appropriate solution for a period of time following removal from the donor animal.
  • the disclosure provides methods for reducing ischemia-reperfusion injury in a cardiac graft subjected to ischemic conditions, the method comprising administering to the graft an effective amount of mitochondria-rich extracellular vesicles within at least about 1 to 2 hours prior to transplantation of the graft into a recipient.
  • the graft has been subjected to ischemic conditions for a period of time, for example, about 3-20 hours, about 3-5 hours, about 3-10 hours, about 10-20 hours, or about 12-18 hours.
  • Also provided are methods for improving the function and/or engraftment of a cardiac graft comprising administering to the graft an effective amount of mitochondria- rich extracellular vesicles prior to transplantation of the graft into a recipient.
  • the mitochondria-rich extracellular vesicles are administered within at least about 1 to 2 hours prior to transplantation of the donor cardiac graft into a recipient.
  • the donor graft is a DCD donor cardiac graft.
  • the terms “donor” and “recipient” refer to the subject that provides the graft and the subject that receives the graft, respectively.
  • the mitochondria-rich extracellular vesicles are heterologous to the recipient.
  • the mitochondria-rich extracellular vesicles are autologous to the recipient.
  • the donor and recipient are each a mammal. In aspects, the donor and recipient are each human.
  • improved function of a cardiac graft may include one or more of improved left ventricular ejection fraction (LVEF), improved left ventricular end-diastolic volume (LVEDV), improved viability, reduced scar formation, reduced fibrosis and reduced apoptosis in the graft.
  • LVEF left ventricular ejection fraction
  • LVEDV left ventricular end-diastolic volume
  • improved viability reduced scar formation, reduced fibrosis and reduced apoptosis in the graft.
  • kits for treating a subject having myocardial injury comprising administering to the subject a therapeutically effective amount of a composition comprising a plurality of mitochondria-rich extracellular vesicles as described herein.
  • the myocardial injury is a result of myocardial ischemia, cardiac surgery, or circulatory arrest.
  • the myocardial injury is myocardial ischemia-reperfusion (IR) injury.
  • the vesicles are administered parenterally.
  • the vesicles are administered via intramyocardial, intracoronary, intravenous, intra- arteriole, or intraventricular injection.
  • treating may include one or more of improved left ventricular ejection fraction (LVEF), improved left ventricular end- diastolic volume (LVEDV), improved viability, reduced scar formation, reduced fibrosis and reduced apoptosis in the cardiac tissue.
  • LVEF left ventricular ejection fraction
  • LVEDV left ventricular end- diastolic volume
  • improved viability reduced scar formation, reduced fibrosis and reduced apoptosis in the cardiac tissue.
  • the subject is a mammal. In aspects, the subject is a human.
  • compositions or pharmaceutical compositions comprising a plurality of mitochondria-rich extracellular vesicles of a donor cell as described herein, for use in the methods described herein.
  • the pharmaceutical compositions may be formulated with one or more pharmaceutically acceptable ingredients including, for example, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, and surfactants.
  • the pharmaceutical composition is sterile.
  • the pharmaceutical compositions comprise a pharmaceutically acceptable carrier, excipient or diluent.
  • the carrier, excipient or diluent is a buffered aqueous solution.
  • the pharmaceutical compositions may be formulated as an aqueous buffered solution having a physiological pH, e.g., a pH in the range of 7-7.4, and isotonic with physiological fluids such as blood, serum, or plasma.
  • a physiological pH e.g., a pH in the range of 7-7.4
  • isotonic with physiological fluids such as blood, serum, or plasma.
  • the pharmaceutical is composition is sterile.
  • extracellular vesicles are nanosized lipid membrane-bound vesicles released from donor cells.
  • extracellular vesicle or “EV” is used herein in accordance with its ordinary and customary meaning in the biomedical arts to refer to nanosized, membrane-bound vesicles released from cells.
  • extracellular vesicles may transport cargo, including DNA, RNA, and proteins, between cells as a form of intercellular communication.
  • Different types extracellular vesicles, including microvesicles and exosomes have been characterized based on their biogenesis or release pathways.
  • the content of extracellular vesicles may include lipids, nucleic acids, proteins, and organelles from donor cells.
  • Microvesicles bud directly from the plasma membrane are typically 100 nanometers (nm) to 1 micrometer (um) in size, and contain cytoplasmic cargo. Exosomes are formed by a fusion of multivesicular bodies and the plasma membrane in which multivesicular bodies release smaller vesicles (exosomes) whose diameters typically range from 40 to 120 nm.
  • the mitochondria-rich extracellular vesicles described herein may be collected from cell culture medium of donor cells, for example by differential centrifugation (e.g., 10,000xg for 30 min).
  • the extracellular vesicles may be isolated from donor cell culture medium by a method comprising one or more of differential centrifugation, ultrafiltration, density gradient/cushion centrifugation, and immunoaffinity-based capture.
  • the cell culture medium is a conditioned medium.
  • the term conditioned medium refers to medium in which donor cells have been cultured for a period of time, for example a period of from 1 to 14 days.
  • the donor cells are peripheral blood mononucleocyte cells (PBMCs).
  • PBMCs may be extracted from whole blood using art recognized methods, for example a Ficoll gradient centrifugation method which separates blood into a top layer of plasma, followed by a layer of PBMCs and a bottom fraction including neutrophils, eosinophils and erythrocytes.
  • the donor cells are induced pluripotent stem cells (iPSC) derived from a PBMC fraction of donor blood.
  • iPSC induced pluripotent stem cells
  • Pluripotency may be induced in the PBMC in accordance with art-recognized methods which include exposing cells cultured in vitro to specific factors that induce pluripotency, for example as described in Takahashi et al., Cell. (2006) 126 (4): 663-76.
  • pluripotency may be induced by exposing the PBMC to Klf4-Oct3/4-Sox2 (KOS) and L-Myc.
  • the donor cells are iPSC that have been differentiated in vitro into cardiomyocytes.
  • the iPSC are differentiated into cardiomyocytes by culturing the iPSC in a base medium, such as Roswell Park Memorial Institute (RPMI) 1640, in the absence of insulin and supplemented with a combination of factors including a B-27TM Supplement, recombinant human albumin, L-asorbic acid 2-phosphate, lactate, the GSK3 inhibitor, CH1R99021, and the Wnt inhibitor, Wnt-C59.
  • the methods include treatment with CHIRR99021 for 2 or 3 days followed by treatment with Wnt-C59 for 2 days.
  • the mitochondria-rich extracellular vesicles are vesicles of cardiomyocytes or vesicles of iPSC.
  • the vesicles express one or more cardiomyocyte marker proteins such as Connexin 43 and endothelial marker CD31.
  • the present inventors previously developed a mitochondrial transplantation therapy using extracellular vesicles secreted from autologous induced pluripotent stem cell (iPSC)- derived cardiomyocytes, as described in W02020232301.
  • iPSC autologous induced pluripotent stem cell
  • the present disclosure demonstrates that human mitochondria-rich extracellular vesicles (MEVs) injected directly into a cardiac graft just prior to transplantation but following 17 hours of storage can substantially reduce myocardial injury and improve graft function.
  • MEVs extracellular vesicles
  • FIG. 1A shows a schematic representation of the experiment.
  • the heart is removed from the donor animal and stored in vitro in University of Wisconsin (UW) solution for 17 hours at 4 °C followed by either sham injection for untreated controls or injection with a dose of 10 8 MEVs or 10 10 MEVs.
  • Cardiac tissue was then assayed for expression of human mitochondrial genes.
  • Rat cardiac tissue was assayed by quantitative PCR one hour after MEV injection. As illustrated in FIG. IB, the data show a dose-dependent increase in the expression of human mitochondrial genes for the two doses of MEVs administered.
  • FIG. 2A Another experiment was conducted to test the effects of MEVs on a cardiac transplant that had been stored after removal from the donor. Similar to the in vitro experiment discussed above, donor heart was removed and stored in vitro in University of Wisconsin (UW) solution for 17 hours at 4 °C followed by either sham injection for untreated controls or injection with MEVs. The donor heart was then transplanted in the recipient animal. Cardiac MRI was used to confirm the spontaneous contraction of the heart and blood flow into the right ventricle at three hours post-transplantation. Cardiac tissue was also visually inspected for the presence of human mitochondria by detecting MitoTrackerTM (MT) labelled mitochondria according to the manufacturer's instructions (Thermo Fisher Scientific). At 3 hours post-transplantation, MT positive mitochondria were detected throughout the entire heart. A schematic representation of the experiment is provided in FIG. 2A.
  • MT MitoTrackerTM
  • FIG. 4A shows representative manganese-enhanced MRI (MEMRI) images acquired 7 days after transplantation and Contrast-to-Noise Ratio (CNR).
  • the contrast effect was analyzed by calculating the difference in CNR between plain MRI T1 -weighted images and manganese- enhanced MRI T1 -weighted images.
  • Noise (N) was measured as the standard deviation of the air signal (Air)
  • background signal (Sbackground) was the mean signal intensity of skeletal muscle near the heart (M)
  • the target signal (Starget) was the mean signal intensity of six sections at the papillary muscle level of the donor heart.
  • CNR was measured as
  • the mean signal intensity of each section was determined using the largest possible circle that did not exceed the boundaries of each section.
  • PC Positive Control
  • MEV and Control groups donor hearts were preserved for 18 hours before transplantation.
  • Tl CNR correlates with myocardial cell viability.
  • high signal intensity on T2-weighted images suggests tissue edema, meaning that T2 CNR correlates with the degree of myocardial injury.
  • FIG. 5A illustrates Tunel staining results obtained 3 hours after transplantation, revealing that the MEV treatment group had a significantly lower rate of cell death compared to the control group.
  • the data are quantified in the bar graph shown in FIG. 5B.
  • cardiomyocytes exposed to ischemia exhibit altered mitochondria, including alterations in structure evidenced by swelling, as well as alterations in function, evidenced by changes in gene and protein expression. Reperfusion of such altered mitochondria induces substantial additional damage leading to cell death in a process of ischemic reperfusion injury. Importantly, the data presented here show that MEV treatment attenuates this ischemic reperfusion injury. [0051] While the invention has been described by means of specific embodiments and applications thereof, modifications and variations could be made thereto by those skilled in the art without departing from the scope set forth in the claims.
  • Section headings are for organizational purposes only and are not to be construed as limiting the subject matter described.
  • a “subject” refers to a mammal, including non-human primates and humans.
  • the subject is a human, a non-human primate, swine, sheep, cow, equine, canine, feline or rodent, including a mouse, rat, a guinea pig or other rodent.
  • treatment refer generally to describe the management and care of a subject, including human and animal subjects (e.g., in veterinary applications), to achieve a therapeutic effect in relation to a disease or disorder, for example, to alleviate, ameliorate, or mitigate one or more symptoms or complications of the disease or disorder, to slow the progression of the disease or disorder, including a reduction in the rate of progression or a halt in the progression, and cure of the condition.
  • treating may include improving mitochondrial function.
  • improved mitochondrial function may include increased intracellular ATP levels, and/or increased expression of PGC-Ia.
  • treating advanced heart failure may include reducing or ameliorating one or more symptoms of advanced heart failure including exercise intolerance, unintentional weight loss, refractory volume overload, recurrent ventricular arrhythmias, hypotension and inadequate perfusion for example manifested as low pulse pressure.
  • an effective amount refers to an amount effective, at dosages and for periods of time necessary to achieve the desired result.
  • an effective amount is an amount that, for example, provides some alleviation, amelioration, mitigation and/or decrease in one or more symptoms of the disease, disorder, or condition experienced by a subject.
  • Effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject.
  • the amount of a given therapeutic agent that will correspond to a therapeutically effective amount will vary depending upon factors including the pharmaceutical formulation, the route of administration, the type or stage of condition, disease or disorder, and subject-specific factors that may include sex, age, race, age, weight, comorbidities, etc. Methods for determining an effective dose are known in the art.
  • the route of administration is an intravenous or parenteral route.
  • Parenteral administration includes, e.g, intramyocardial, intracoronary, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.

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  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Developmental Biology & Embryology (AREA)
  • Cell Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Vascular Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés de réduction d'une lésion d'ischémie-reperfusion dans un greffon cardiaque par administration au greffon ex vivo d'une composition comprenant des vésicules extracellulaires riches en mitochondries. L'invention concerne également des procédés associés pour améliorer la fonction d'un greffon cardiaque et des compositions et des procédés associés.
PCT/US2025/020328 2024-03-18 2025-03-18 Procédés d'amélioration de la fonction de greffon cardiaque Pending WO2025199076A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202463566662P 2024-03-18 2024-03-18
US63/566,662 2024-03-18
US202463572992P 2024-04-02 2024-04-02
US63/572,992 2024-04-02

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WO2025199076A1 true WO2025199076A1 (fr) 2025-09-25

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10370458B2 (en) * 2016-01-15 2019-08-06 Children's Medical Center Corporation and Beth Israel Therapeutic use of mitochondria and combined mitochondrial agent
WO2020232301A1 (fr) 2019-05-15 2020-11-19 The Board Of Trustees Of The Leland Stanford Junior University Procédés et compositions pour le traitement des cardiomyocytes
US20220347212A1 (en) * 2019-05-02 2022-11-03 Children`S Medical Center Corporation Prophylactic and therapeutic use of mitochondria and combined mitochondrial agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10370458B2 (en) * 2016-01-15 2019-08-06 Children's Medical Center Corporation and Beth Israel Therapeutic use of mitochondria and combined mitochondrial agent
US20220347212A1 (en) * 2019-05-02 2022-11-03 Children`S Medical Center Corporation Prophylactic and therapeutic use of mitochondria and combined mitochondrial agents
WO2020232301A1 (fr) 2019-05-15 2020-11-19 The Board Of Trustees Of The Leland Stanford Junior University Procédés et compositions pour le traitement des cardiomyocytes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BERNHARD DORWEILER ET AL: "Ischemia-Reperfusion Injury; Pathophysiology and Clinical Implications", EUROPEAN JOURNAL OF TRAUMA AND EMERGENCY SURGERY ; OFFICIAL PUBLICATION OF THE EUROPEAN TRAUMA SOCIETY, URBAN & VOGEL, MU, vol. 33, no. 6, 20 November 2007 (2007-11-20), pages 600 - 612, XP019565282, ISSN: 1863-9941, DOI: 10.1007/S00068-007-7152-Z *
SUH JOONHO ET AL: "Mitochondria as secretory organelles and therapeutic cargos", EXPERIMENTAL AND MOLECULAR MEDICINE, vol. 56, no. 1, 4 January 2024 (2024-01-04), GB, pages 66 - 85, XP093289893, ISSN: 2092-6413, Retrieved from the Internet <URL:https://www.nature.com/articles/s12276-023-01141-7> DOI: 10.1038/s12276-023-01141-7 *
TAKAHASHI ET AL., CELL, vol. 126, no. 4, 2006, pages 663 - 76

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