WO2023165582A1 - Système et procédé d'administration ciblée - Google Patents

Système et procédé d'administration ciblée Download PDF

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Publication number
WO2023165582A1
WO2023165582A1 PCT/CN2023/079438 CN2023079438W WO2023165582A1 WO 2023165582 A1 WO2023165582 A1 WO 2023165582A1 CN 2023079438 W CN2023079438 W CN 2023079438W WO 2023165582 A1 WO2023165582 A1 WO 2023165582A1
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Prior art keywords
lipids
cholesterol
following components
ionizable
structured
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PCT/CN2023/079438
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English (en)
Chinese (zh)
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孙怡迪
周昌阳
毛少帅
彭文博
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益杰立科(上海)生物科技有限公司
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Publication of WO2023165582A1 publication Critical patent/WO2023165582A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This application relates to the field of biomedicine, in particular to a lipid delivery carrier and delivery method for the central nervous system.
  • cerebrospinal fluid moves unidirectionally from the ventricles outward, but moves multidirectionally in the subarachnoid space. Eventually drains into the venous system, diluting macromolecules, lipids, and insoluble molecules into the blood.
  • the blood circulation is a non-Newtonian fluid while the cerebrospinal fluid circulation is a Newtonian fluid mainly affected by Brownian motion. Fluctuation dynamics follow the laws of the fluctuation-dissipation theorem (unlike blood). Its translation and rational motion in CSF are based on the Stokes-Einstein and Stokes-Einstein-Debye relational equations.
  • lipid components in non-CNS cell membranes phospholipids, cholesterol, glycoproteins, carbohydrate groups.
  • sphingolipids, glycosphingolipids, and sialic acid are mainly found in gangliosides, which play an important role in regulating neuronal plasticity in glycosides compared with other types of cells. role.
  • sialic acid acts as a cellular receptor (with a specific protein: GPI-nexin) attached to the outer leaflet of the plasma membrane to facilitate signal transduction, neurotransmission, interaction with neuroregulatory proteins, and cell-cell recognition and proliferation.
  • LNP low-density lipoprotein
  • the present application provides a method for delivering nucleic acids to cells in the central nervous system using lipid nanoparticles, which can remain stable under specific pH and protein concentration environments such as cerebrospinal fluid; the lipid nanoparticles are based on The construction of nerve cell membrane components is conducive to its fusion with nerve cell membranes, mediating entry into cells, and releasing embedded nucleic acids such as mRNA.
  • the present invention is based in part on the surprising discovery that lipid- or polymer-based nanoparticles loaded with nucleic acid molecules can be administered directly into the CNS space (e.g., by intrathecal administration) and efficiently penetrate neuronal cell membranes, resulting in nucleic acid molecules in the CNS space. Intracellular delivery in neurons in the brain and/or spinal cord.
  • the lipid- or polymer-based nanoparticles described in this application can effectively deliver nucleic acid molecules into the cells of the central nervous system, even neurons located deep in the center of the brain and spine and those difficult to treat. motor neuron.
  • the present invention provides an improved and efficient method for CNS delivery of nucleic acid drugs and holds promise as an effective therapy for the treatment of a variety of CNS diseases.
  • the application provides the use of a lipid nanoparticle (LNP) delivery system in the preparation of a drug for the prevention and/or treatment of the central nervous system, wherein the LNP comprises the following components in terms of molar percentage: ionizable lipid Cholesterol-based lipids 37.5%-45%, structured lipids 9-10%, pegylated lipids 1.5%-2.5%.
  • LNP lipid nanoparticle
  • said LNP comprises the following components: about 45-50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, pegylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids %-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 10% structured lipids, 1.5%-pegylated lipids 2.5%.
  • LNP comprises the following components: about 45-50% ionizable lipids, 38.5%-45% cholesterol-based lipids, 9-10% structured lipids, PEGylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 38.5-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9% structured lipids, 1.5%-2.5% pegylated lipids %.
  • the ionizable lipid is selected from MC-3, LPO1 and combinations thereof.
  • the structural lipid is selected from DPPC, DSPC, DOPE and combinations thereof.
  • the PEGylated lipid is selected from DAG-PEG, DAA-PEG, DMG-PEG, DSPE-PEG, C8-PEG, DOG-PEG, ceramide PEG, and combinations thereof.
  • the cholesterol-based lipid comprises cholesterol or PEGylated cholesterol.
  • said liposome comprises a combination selected from:
  • LP01 cholesterol, DOPE, DMG-PEG;
  • MC3/LP01 cholesterol
  • DSPC DMG-PEG
  • the present application provides a method of delivering a therapeutic agent to the central nervous system (CNS), comprising: intrathecally administering to a subject in need of delivery a combination comprising a therapeutic agent encapsulated within a lipid nanoparticle wherein the lipid nanoparticle comprises the following components based on molar percentages: about 45-50% ionizable lipids, 37.5%-45% cholesterol-based lipids, 9-10% structured lipids, polyethylene Diolated lipids 1.5%-2.5%.
  • CNS central nervous system
  • said LNP comprises the following components: about 45-50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, pegylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids %-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 10% structured lipids, 1.5%-pegylated lipids 2.5%.
  • LNP comprises the following components: about 45-50% ionizable lipids, 38.5%-45% cholesterol-based lipids, 9-10% structured lipids, PEGylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 38.5-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9% structured lipids, 1.5%-2.5% pegylated lipids %.
  • the cells in the brain and/or spinal cord are selected from motor neurons, oligodendrocytes, oligodendrocytes, astrocytes, glial cells, Anterior horn cells and dorsal root ganglia and combinations thereof.
  • the therapeutic agent comprises a nucleic acid
  • the nucleic acid is selected from siRNA, miRNA, pri-miRNA, messenger RNA (mRNA), clustered regularly interspaced short palindromic repeat (CRISPR)-related nucleic acid, single guide RNA (sgRNA) ), CRISPR-RNA (crRNA), trans-activating crRNA (tracrRNA), plasmid DNA (pDNA), transfer RNA (tRNA), antisense oligonucleotide (ASO), guide RNA, double-stranded DNA (dsDNA), single One or more of stranded DNA (ssDNA), single stranded RNA (ssRNA) and double stranded RNA (dsRNA).
  • siRNA siRNA
  • miRNA messenger RNA
  • mRNA messenger RNA
  • CRISPR clustered regularly interspaced short palindromic repeat
  • sgRNA single guide RNA
  • crRNA CRISPR-RNA
  • tracrRNA trans-activating crRNA
  • pDNA plasmid DNA
  • the therapeutic agent comprises mRNA.
  • intracellular delivery of said mRNA results in intracellular expression of said protein encoded by said mRNA within the cytosol of said neuron.
  • the intracellular delivery of the mRNA results in the expression of the protein encoded by the mRNA and, after expression, secretion from the neuron to the outside of the cell.
  • the ionizable lipid is selected from MC-3, LPO1 and combinations thereof.
  • the structural lipid is selected from DPPC, DSPC, DOPE and combinations thereof.
  • the PEGylated lipid is selected from DAG-PEG, DAA-PEG, DMG-PEG, DSPE-PEG, C8-PEG, DOG-PEG, ceramide PEG, and combinations thereof.
  • the cholesterol-based lipid comprises cholesterol or PEGylated cholesterol.
  • said liposome comprises a combination selected from:
  • LP01 cholesterol, DOPE, DMG-PEG;
  • MC3/LP01 cholesterol
  • DSPC DMG-PEG
  • the present application provides a composition for treating central nervous system diseases or disorders, which comprises lipid nanoparticles encapsulated with therapeutic agents, wherein the lipid nanoparticles comprise the following Components: ionizable lipids approximately 45-50%, cholesterol-based lipids 37.5%-45%, structured lipids 9-10%, pegylated lipids 1.5%-2.5%.
  • said LNP comprises the following components: about 45-50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, pegylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids %-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 10% structured lipids, 1.5%-pegylated lipids 2.5%.
  • LNP comprises the following components: about 45-50% ionizable lipids, 38.5%-45% cholesterol-based lipids, 9-10% structured lipids, PEGylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 38.5-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9% structured lipids, 1.5%-2.5% pegylated lipids %.
  • it is formulated as a liquid suitable for administration in cerebrospinal fluid.
  • it is formulated for administration by intrathecal injection.
  • the intrathecal injection comprises injection into the hippocampal region of the brain parenchyma, intracerebroventricular injection and/or spinal orthotopic injection.
  • the disease or disorder of the central nervous system comprises Parkinson's syndrome, Angelman syndrome or spinal cord injury disease.
  • the present application provides a method for treating a central nervous system disease or disorder, comprising administering lipid nanoparticles comprising a therapeutic agent to the cerebrospinal fluid of the subject, wherein the lipid
  • the nanoparticles comprise the following components: ionizable lipids approximately 45-50%, cholesterol-based lipids 37.5%-45%, structured lipids 9-10%, and pegylated lipids 1.5%-2.5%.
  • said LNP comprises the following components: about 45-50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, pegylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids %-2.5%.
  • said LNP comprises the following components: about 50% ionizable lipids, 37.5%-38.5% cholesterol-based lipids, 10% structured lipids, 1.5%-pegylated lipids 2.5%.
  • LNP comprises the following components: about 45-50% ionizable lipids, 38.5%-45% cholesterol-based lipids, 9-10% structured lipids, PEGylated lipids Quality 1.5%-2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 38.5-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9-10% structured lipids, 1.5% pegylated lipids -2.5%.
  • said LNP comprises the following components: about 45% ionizable lipids, 44-45% cholesterol-based lipids, 9% structured lipids, 1.5%-2.5% pegylated lipids %.
  • it is formulated as a liquid suitable for administration in cerebrospinal fluid.
  • said administering comprises intrathecal injection.
  • the intrathecal injection comprises injection into the hippocampal region of the brain parenchyma, intracerebroventricular injection and/or spinal orthotopic injection.
  • the disease or disorder of the central nervous system comprises Parkinson's syndrome, Angelman syndrome or spinal cord injury disease.
  • Figure 1 shows the results of transfection of the lipid nanoparticles described in this application into the striatum of Ai9 transgenic mice.
  • Figure 2 shows the evaluation of transfection effect by spinal injection in mice.
  • Figure 3 shows the transfection evaluation of spinal injection in adult mice.
  • FIG. 4 shows is that the lipid nanoparticle transfection Ai9 transgenic mouse brain result map described in the application
  • LNP nanoparticles are prepared to achieve effective embedding of gene editing tools or other nucleic acid drugs.
  • the organic phase contains at least one ionizable lipid, at least one supporting lipid, at least one amphiphilic block copolymer and cholesterol, and is dissolved by an organic solvent that is miscible with water.
  • the organic solvent is preferably selected from ethanol, acetonitrile, acetone and the like.
  • Aqueous phase an aqueous solution of gene editing tools, wherein the content of nucleic acid substances (such as mRNA) is 0.5-50% (w/v), and the pH is 3.0-7.0.
  • the aqueous salt solution is selected from: citrate buffer, phosphate buffer, Tris-HCl buffer system.
  • the mixing of organic phase and aqueous phase can be achieved by microfluidic and impinging flow reactors.
  • the embedding efficiency of gene editing tool RNA can be optimized by adjusting the N/P ratio of the system, and the N/P ratio is 1:1 to 9:1.
  • LNP was prepared by the method of Example 1.1, and LNP was prepared by regulating the molar ratio of ionizable lipid and cationic lipid, and its embedding rate for more than 2000bp mRNA was characterized.
  • RNA is derived from RNA extracted from yeast, purchased from McLean, Cat. No. R822593
  • the embedding rate of prepared LNP is determined by Quant-iTTM RNA Reagent and Kit assay.
  • Solution configuration Dilute an appropriate amount of 20 ⁇ TE buffer solution to 1 ⁇ with ultrapure water, which is enough for the day’s experiment. Dilute the concentrated dye solution with 1 ⁇ TE (large range 25-1000ng/ml RNA) at a ratio of 1:200, (small range 1-50ng/ml RNA) at a ratio of 1:2000. Wrap it in gold foil or store it in a dark place away from light. Dilute TritonX-100 to 5% concentration with 1 ⁇ TE buffer for use.
  • Sample processing set ultrapure water with RNA concentration of 0 as the blank background, set TE buffer instead of LNP with 5% TritonX-100 as the free RNA assay sample, and set LNP with 5% TritonX-100 as the total RNA assay Sample. Take the LNP sample to be determined and add an equal volume of 5% TritonX-100, 1 ⁇ TE solution to the blank, and incubate at 50-60°C for 5-10 minutes.
  • the incubated LNP samples were diluted to 10-400 times with 1 ⁇ TE buffer solution (appropriately adjusted according to the RNA concentration of the sample group). After dilution, 100 ⁇ l was added to a 96-well plate, and then 100 ⁇ l of the diluted concentrated dye solution was added in the dark, and the fluorescence absorbance was measured within 5 minutes.
  • the measurement conditions are an excitation wavelength of 480 nm and an emission wavelength of 520 nm.
  • Lipid nanoparticles were prepared by formula #2 in Table 1, and Cre mRNA was embedded (the Cre mRNA sequence is GenBank: AAL31698.1, and the Cre mRNA sequences used in subsequent examples are all of this sequence).
  • Stereotaxic injections of Ai9 transgenic mice were performed using a standard stereotaxic apparatus (Model 68528, RWD Life Sciences) under isoflurane anesthesia (4% induction and 2% maintenance) or 5% chloral hydrate.
  • the mouse skull was exposed and cleaned, a small craniotomy was performed, and a pulled glass micropipette manufactured by a micropipette stretcher (Shutter Instrument Co.) was placed in the striatum (experimental group: A/P+1.2 mm; M/L: 2.0mm; D/V 3.0mm). Subsequently, we injected 1uL of LNP sample (100ng/ul mRNA-embedded LNP at a speed of 120nL/min) through a pressure microinjector (KDS-310-plus, KD Scientific). Leave the injection needle in place for 5 min before slowly withdrawing to allow the LNP to diffuse.
  • LNP sample 100ng/ul mRNA-embedded LNP at a speed of 120nL/min
  • KDS-310-plus, KD Scientific a pressure microinjector
  • LNP can effectively transfect the striatum of the injected area, showing obvious red fluorescence. And compared to neuron cells (neuron), LNP transfected more glial cells (Glial cells), showing that it can be efficiently delivered to the central nervous system (brain tissue) to treat central nervous diseases such as Parkinson's.
  • the mouse spine was taken 5 days after injection for confocal laser, and the results showed that LNP can effectively transfect the P0 mouse spine (Figure 2), proving that it has the potential of efficient delivery to the central nervous system (spinal cord) for Angelman syndrome Gene therapy for rare diseases.
  • mice were anesthetized with 1% sodium pentobarbital at a ratio of 0.16 mL/24 g. After the mouse was anesthetized, the hair around the injured part of the back of the mouse was shaved with a shaver; a small incision was made at the exposed epidermis to fully expose the subcutaneous tissue; Stretch the tissue to expose the spine, use micro forceps to break the lamina along the intervertebral space or use micro scissors to cut the lamina along the intervertebral space to expose the spinal cord, inject #2 formula LNP at the T8-T10 position , each mouse was injected with 2uL sample (concentration 100ng/uL).
  • Lipid nanoparticles were prepared using recipe #7 in Table 1, and samples of Cre mRNA were embedded at the same time.
  • Stereotaxic injections were performed on Ai9 transgenic adult mice using a standard stereotaxic apparatus (Model 68528, RWD Life Sciences) under isoflurane anesthesia (4% induction and 2% maintenance) or 1.25% tribromoethanol.
  • the mouse skull was exposed and cleaned, and a cranial drill was used to perforate the skull, and a glass micropipette made by a micropipette stretcher (Shutter Instrument Co.) was placed in the hippocampus (experimental group, control group: AP- 2.00mm; ML+-1.5mm; DV-1.5mm).
  • LNP samples 2 uL of LNP samples were injected (at a rate of 300 nL/min) via a pressure microsyringe (Nanoject III, Drummond). Leave the injection needle in place for 5 minutes before slowly withdrawing it, allowing the LNP to seep down the needle.
  • the mice Four days after the injection, the mice were sacrificed under the conditions of animal welfare, and the brain slices were taken, and observed through a laser section rapid scanning microscope (VS200, Olympus). The results showed that LNP can effectively transfect parts of the CA3 and DG regions in the hippocampal structure Granulosa cells and glial cells (Figure 4). It has been shown to be effectively delivered to the central nervous system (brain tissue) for the treatment of related central system diseases.

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Abstract

L'invention concerne l'utilisation d'un système d'administration de nanoparticules lipidiques (LNP) dans la préparation d'un médicament pour la prévention et/ou le traitement d'une maladie du système nerveux central, les LNP comprenant les composants suivants sur la base d'un pourcentage molaire : d'environ 45 % à 50 % de lipide ionisable, de 37,5 % à 45 % de lipide à base de cholestérol, de 9 % à 10 % de lipide structural et de 1,5 % à 2,5 % de lipide pégylé.
PCT/CN2023/079438 2022-03-04 2023-03-03 Système et procédé d'administration ciblée WO2023165582A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167922A (zh) * 2016-11-08 2019-08-23 特拉维夫大学拉莫特有限公司 用于核酸递送的阳离子脂质及其制备
CN113286882A (zh) * 2018-11-09 2021-08-20 阿布特斯生物制药公司 脂质纳米颗粒制剂
CN113645960A (zh) * 2019-01-17 2021-11-12 佐治亚技术研究公司 含有氧化的胆固醇的药物递送系统
CN113636947A (zh) * 2015-10-28 2021-11-12 爱康泰生治疗公司 用于递送核酸的新型脂质和脂质纳米颗粒制剂
CN113728101A (zh) * 2018-11-09 2021-11-30 阿布特斯生物制药公司 脂质纳米颗粒制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113636947A (zh) * 2015-10-28 2021-11-12 爱康泰生治疗公司 用于递送核酸的新型脂质和脂质纳米颗粒制剂
CN110167922A (zh) * 2016-11-08 2019-08-23 特拉维夫大学拉莫特有限公司 用于核酸递送的阳离子脂质及其制备
CN113286882A (zh) * 2018-11-09 2021-08-20 阿布特斯生物制药公司 脂质纳米颗粒制剂
CN113728101A (zh) * 2018-11-09 2021-11-30 阿布特斯生物制药公司 脂质纳米颗粒制剂
CN113645960A (zh) * 2019-01-17 2021-11-12 佐治亚技术研究公司 含有氧化的胆固醇的药物递送系统

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