WO2025054580A1 - Compositions et procédés pour augmenter la formation capillaire myocardique, réduire l'hypertrophie ventriculaire gauche et/ou réduire un dysfonctionnement ventriculaire - Google Patents

Compositions et procédés pour augmenter la formation capillaire myocardique, réduire l'hypertrophie ventriculaire gauche et/ou réduire un dysfonctionnement ventriculaire Download PDF

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WO2025054580A1
WO2025054580A1 PCT/US2024/045782 US2024045782W WO2025054580A1 WO 2025054580 A1 WO2025054580 A1 WO 2025054580A1 US 2024045782 W US2024045782 W US 2024045782W WO 2025054580 A1 WO2025054580 A1 WO 2025054580A1
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mdm2
mybpc3
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WO2025054580A9 (fr
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Jason Robert BECKER
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University of Pittsburgh
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    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • C12N9/222—Clustered regularly interspaced short palindromic repeats [CRISPR]-associated [CAS] enzymes
    • C12N9/226—Class 2 CAS enzyme complex, e.g. single CAS protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y203/00—Acyltransferases (2.3)
    • C12Y203/02—Aminoacyltransferases (2.3.2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]

Definitions

  • HCM hypertrophic cardiomyopathy
  • LV left ventricular
  • HCM hypertrophic cardiomyopathy
  • MYBPC3 myosin binding protein C3
  • MYH7 myosin heavy chain 7
  • mutations in these 2 genes account for approximately 80% of mutation-positive HCM cases.
  • the cause of myocardial hypertrophy in HCM is increased cardiomyocyte growth that occurs during childhood or in adult life in humans.
  • Microvascular dysfunction or disease occurs secondary to abnormalities of the capillary beds of multiple different organs such as the brain, kidney, retina, skin, lung, and heart. MVD has been consistently identified in many different forms of human cardiomyopathy secondary to both ischemic and nonischemic etiologies.
  • G Representative myocardial blood flow velocity tracings using pulsed wave Doppler echocardiography in postnatal day 60 WT and Mybpc3-/- mice. Myocardial blood flow at baseline and after retro-orbital injection with adenosine (postadenosine) to induce maximal hyperemia.
  • H Myocardial blood flow in postnatal day 60 WT after adenosine (right bars) were normalized to heart weight.
  • CD31 indicates cluster of differentiation 31; DAPI, 4',6-diamidino-2-phenylindole; H&E, hematoxylin-eosin; IHC, immunohistochemistry; Mybpc3-/-, cardiac myosin binding protein 3 homozygous deletion; Post-Ado, post adenosine; TIE2, TEK receptor kinase; WGA, wheat germ agglutinin; and WT, wild-type.
  • FIG. 2(A-G) shows dynamic changes in HIFla and HIF2a occur during the early postnatal period in the Mybpc3-/- myocardium.
  • P2 postnatal day 2
  • P7 postnatal day 7
  • P25 postnatal day 25
  • CM indicates cardiomyocyte
  • DAPI 4',6-diamidino-2- phenylindole
  • HIFla hypoxia-inducible factor 1 alpha
  • HIF2a hypoxia-inducible factor 2 alpha
  • Mybpc3-/- cardiac myosin binding protein 3 homozygous deletion
  • WT wild-type.
  • Figure 3(A-R) shows the noncanonical degradation of HIFla in the Mybpc3-/- myocardium is regulated by cardiomyocyte MDM2.
  • M Immunoblot for MDM2, HIFla, HIF2a, MYPBC3, and P-actin in left ventricular tissue from P7 WT, Mybpc3-/-, Mybpc3-/-/Myh6:Cre, and Mybpc3-/-Mdm2fl/+/Myh6:Cre mice.
  • BTZ indicates bortezomib; DAPI, 4', 6- diamidino-2-phenylindole; HC, heavy chain; HIFl , hypoxia-inducible factor 1 alpha; HIF2a, hypoxia-inducible factor 2 alpha; IB, immunoblot; LC, light chain; MDM2, murine double minute 2; Mdm2fl/+, Mdm2 heterozygous floxed; Mybpc3-/-, cardiac myosin binding protein 3 homozygous deletion; Myh6:Cre, myosin heavy chain 6:Cre recombinase; Poly-Ub, K48-linked ubiquitin; Rpl32; ribosomal protein L32; Ub, Ubiquitin; VHL, Von Hippel-Lindau; and WT, wild-type.
  • FIG. 4(A-O) shows increased HIF2a in the Mybpc3-/- myocardium occurs secondary to MDM2 facilitated degradation of VHL.
  • (D) Representative immunohistochemistry images for CD3 costained with WGA in left ventricular tissue from P7 Myh6:MerCreMer (MCM) and Hiflafl/flMCM mice injected with tamoxifen at postnatal days 1 (Pl) and 4 (P4). Nuclei are blue (DAPI); scale bars 50 pm.
  • FIG. 8(A-F) shows reduced postnatal capillary formation in the Mybpc3-/- myocardium.
  • H [Top] Representative H&E-stained mid- ventricular LV tissue cross-sections with LCA magnified in WT and Mybpc3-/- mice at P2 or P7.
  • K Representative myocardial blood flow velocity tracing in LCA using pulsed wave Doppler.
  • Figure 10(A-O) shows alterations in MDM2 gene expression and MDM2 protein levels in Mybpc3-/- mice.
  • F Immunoblots for HIFla and P-actin in EV tissue from P7 Mybpc3-/- vehicle and Mybpc3-/- injected with PHD inhibitor (Molidustat, 10 mg/kg) from Pl to P6.
  • FIG 11 shows that VHL NEDD8 post- translational modifications are not altered in Mybpc3-/- mice.
  • Representative in situ proximity ligation assay (PLA) images for secondary antibody PLA probes only (+/-), MDM2 antibody and probes, and VHL antibody and probes in LV tissue from P7 WT mice. Scale bars 25 pm.
  • PHA in situ proximity ligation assay
  • Figure 12(A-M) shows genetic reduction of MDM2 protein levels in cardiomyocytes prevents the development of left ventricular hypertrophy and systolic dysfunction in Mybpc3-/- mice.
  • LVPWd LV posterior wall thickness at end diastole
  • LVIDd LV internal diameter at end diastole
  • FS LV fractional shortening
  • FIG. 13(A-P) shows Myh6R404Q/WT mice have reduced left ventricular capillaries and VHL protein levels.
  • A Amino acid comparison between human MYH7 WT and R403Q mutation and the mouse MYH6 WT and R404Q mutation.
  • B Chromatogram of DNA sequencing from WT and Myh6R404Q/WT mice. The mutated base pairs create the R404Q amino acid change and the remaining base pair mutations are silent DNA changes which facilitate genotyping and prevent CRISPR/Cas9 mediated cutting of the donor DNA.
  • (K) Representative immunohistochemistry images for the DNA damage marker yH2AX and cardiomyocyte (CM) nuclei marker pericentriolar material 1 (PCM1) in LV tissue from P7 WT and Myh6R404Q/WT mice. Scale bars 25 pm.
  • (M) Representative immunohistochemistry images for yH2AX and endothelial cell (EC) marker CD31 in LV tissue from P7 WT and Mybpc3-/- mice. Scale bars 10 pm.
  • Figure 14(A-D) shows genetic reduction of cardiomyocyte MDM2 protein levels improves myocardial capillary density and myocardial coronary flow reserved in Myh6R404Q/WT mice.
  • FIG. 15(A-M) shows MD-224 reduces left ventricular cardiomyocyte size and myocardial hypertrophy with improvement in left ventricular systolic function in Mybpc3-/- and Myh6R404Q/WT mice.
  • G Representative myocardial blood flow velocity tracings from pulsed wave Doppler echocardiography of P60 Myh6R404Q/WT mice injected with vehicle or MDM2 PROTAC (MD-224) from Pl to P24.
  • the E3 ligase MDM2 (murine double minute 2) has been shown to ubiquitinate HIFla.33 Therefore, we wanted to determine whether MDM2 was regulating the ubiquitination of HIFla in Mybpc3-/- cardiomyocytes.
  • MDM2 protein levels we measured MDM2 protein levels and discovered that MDM2 protein levels were increased in Mybpc3-/- LV tissue during the same time point (postnatal day 7) when HIFla protein was decreased (Figure 3J and 3K).
  • Mybpc3-/- mice rapidly develop LVH and LV dysfunction in the early postnatal time period. Therefore, we measured cardiac structure and function in Mybpc3-/- mice with reduction of cardiomyocyte MDM2.
  • targeted elimination of cardiomyocyte HIFla and HIF2a did not cause significant changes in cardiac structure or function in the early postnatal time period (Figure 12H through 12M).
  • Example 7 MDM2 Regulates Capillary Formation Before the Development of Ventricular Hypertrophy in Myh6R404Q/WT Mice
  • the murine MYH6 protein is targeted because it is the dominant myosin heavy chain protein in the adult mouse LV versus MYH7 in the adult human LV and this strategy was successfully used in the past with homologous recombination methods.
  • Mybpc3-/- mice that rapidly develop LVH by postnatal day 7
  • heterozygote Myh6R404Q/WT mice had normal LV wall thickness through postnatal day 25 but developed LVH by postnatal day 60 without systolic dysfunction (Figure 6A through 6C; Figure 13C).
  • Male and female Myh6R404Q/WT mice developed similar levels of LVH by postnatal day 60 but male mice had slightly more LVH by 6 months of age (Figure 13D through 13G).
  • Myh6R404Q/WT myocardium had an increase in MDM2 protein (Figure 6J and 6K). Similar to Mybpc3-/- mice, the increase in MDM2 in the Myh6R404Q/WT mice was associated with increased cardiomyocyte DNA damage ( Figure 13K and 13L). Importantly, we found no evidence of increased endothelial cell DNA damage ( Figure 13M and 13N). We then measured HIF 1 a and HIF2a protein levels and discovered that postnatal day 7 Myh6R404Q/WT myocardium had reduced HIFla and increased HIF2a protein levels ( Figure 61, 6L, and 6M).
  • transient chemical targeting of MDM2 prevented the development of LVH in the Myh6R404Q/WT model at postnatal day 60 (Figure 15H through 15M).
  • these findings show that transient chemical targeting of MDM2 prevents the HIF imbalance and myocardial capillary dysfunction in 2 unrelated models of HCM.
  • Myocardial MVD has been identified in multiple different forms of human cardiomyopathy and is often thought to occur as a consequence of the pathologic myocardial remodeling process.
  • Myocardial MVD has been demonstrated in humans with hypertrophic cardiomyopathy (HCM) and is thought to be a significant contributor to disease pathogenesis.
  • HCM hypertrophic cardiomyopathy
  • HCM hypertrophic cardiomyopathy
  • the reduction in myocardial capillary formation in HCM is caused by the E3 ligase MDM2 inducing an imbalance of cardiomyocyte HIFla and HIF2a protein levels during the early postnatal time period.
  • myocardial MVD can precede the development of myocardial hypertrophy in HCM and selective targeting of MDM2 prevents myocardial MVD from developing.
  • This study identified a key regulatory mechanism controlling the development of myocardial MVD and provides unique insights into molecular pathways contributing to the pathophysiology of HCM. [0098]
  • MDM2 as a critical regulator of MVD in HCM by reducing myocardial angiogenesis in the early postnatal heart.
  • MDM2 has not been previously shown to regulate MVD in the heart or other organ systems.
  • increased expression of MDM2 has been shown to play a proangiogenic role in malignant tissues.
  • the divergent pro- and antiangiogenic properties of MDM2 appear to be partially explained by the acute versus chronic overexpression of the protein.
  • the chronic overexpression of MDM2 in malignant tissues can lead to increased p53 degradation which facilitates proangiogenic gene expression.
  • the acute increase in cardiomyocyte MDM2 in our HCM models led to an antiangiogenic role for this protein through its role in simultaneously regulating the protein stability of HIF1 a and HIF2a.
  • MDM2 concurrently regulated the noncanonical degradation of HIFla and the canonical degradation of HIF2a leading to an imbalance in these proteins.
  • MDM2 can regulate HIF 1 a ubiquitination in cancer cell lines, but our data indicates this noncanonical mechanism of HIF1 a degradation is important in vivo in a nonmalignant context.
  • in-vivo cardiomyocyte MDM2 can bind and regulate the ubiquitination of VHL leading to a reduction in the canonical degradation of HIF2a.
  • MDM2 as a specific regulator of HIF and VHL protein stability in the early stages of HCM and reinforces the increasing evidence that the ubiquitin-proteosome system is an important regulator in HCM.
  • MDM2 can also regulate VHL neddylation in cancer cell lines.
  • MDM2 dynamically regulated VHL neddylation in vivo in our disease model.
  • HIFla and HIF2a have opposing roles in regulating myocardial capillary formation in the postnatal mammalian heart, with HIFla serving a proangiogenic role and HIF2a serving an antiangiogenic role.
  • HIFla and HIF2a are more often reported to have synergistic roles in promoting angiogenesis.
  • Our data shows that the regulation of organ angiogenesis by HIFla and HIF2a is highly dependent on cell type and tissue environment. This study adds to the growing data that cardiomyocyte HIF signaling has distinct roles in regulating myocardial growth and maturation depending on the developmental time point when they are expressed.

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Abstract

L'invention concerne des méthodes de traitement d'une cardiomyopathie et/ou d'un dysfonctionnement microvasculaire myocardique, d'augmentation de la croissance capillaire myocardique, de réduction de l'hypertrophie ventriculaire gauche et/ou de réduction d'un dysfonctionnement ventriculaire gauche chez un sujet comprenant l'administration d'un inhibiteur de MDM2 au sujet.
PCT/US2024/045782 2023-09-08 2024-09-09 Compositions et procédés pour augmenter la formation capillaire myocardique, réduire l'hypertrophie ventriculaire gauche et/ou réduire un dysfonctionnement ventriculaire Pending WO2025054580A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160339019A1 (en) * 2014-01-28 2016-11-24 Buck Institute For Research On Aging Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders
WO2022117049A1 (fr) * 2020-12-02 2022-06-09 四川大学华西医院 Utilisation d'immunocyte de car nkg2d dans le traitement anti-âge et de maladies liées à l'âge
WO2022221051A1 (fr) * 2021-04-11 2022-10-20 President And Fellows Of Harvard College Myocytes cardiaques et compositions et procédés de production associés
WO2023076665A1 (fr) * 2021-11-01 2023-05-04 Imbria Pharmaceuticals, Inc. Méthodes de traitement d'affections cardiovasculaires et méthodes d'augmentation de l'efficacité du métabolisme cardiaque

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160339019A1 (en) * 2014-01-28 2016-11-24 Buck Institute For Research On Aging Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders
WO2022117049A1 (fr) * 2020-12-02 2022-06-09 四川大学华西医院 Utilisation d'immunocyte de car nkg2d dans le traitement anti-âge et de maladies liées à l'âge
WO2022221051A1 (fr) * 2021-04-11 2022-10-20 President And Fellows Of Harvard College Myocytes cardiaques et compositions et procédés de production associés
WO2023076665A1 (fr) * 2021-11-01 2023-05-04 Imbria Pharmaceuticals, Inc. Méthodes de traitement d'affections cardiovasculaires et méthodes d'augmentation de l'efficacité du métabolisme cardiaque

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