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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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  • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6905—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
  • A61K47/6911—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
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  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
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  • 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
  • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
  • A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
  • A61K47/6929—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
• • 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
  • A61K48/0008—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 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
  • A61K48/0025—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 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
  • A61K48/0033—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 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
• • 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
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/5123—Organic compounds, e.g. fats, sugars
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
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  • 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
  • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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  • 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
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  • 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]
• • C—CHEMISTRY; METALLURGY
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  • C12N2320/00—Applications; Uses
  • C12N2320/30—Special therapeutic applications
  • C12N2320/32—Special delivery means, e.g. tissue-specific

Definitions

• Fig. 10B is a representative immunofluorescence images of liver section showed that tdTomato signal was mainly expressed in liver hepatocytes. (Scale bar: 20 ⁇ m).
• Fig. 22B shows IVIS images showed that the N-series LNPs mediated specific delivery of fLuc mRNA to the lungs.
• Fig. 27 is a Venn diagram showing common and unique proteins absorbed on 306- O12B LNP (light green) and 306-N16B LNP (light blue).
• LNPs can selectively govern the adsorption of specific plasma proteins to serve as targeting ligands that direct LNPs to selected organs.
• proteomics a group of unique plasma proteins was identified that specifically absorbed on the surface of two representative LNP candidates, 306-012B and 306-N16B, that may affect the targetability of these LNPs.
• different pulmonary subcellular populations can be targeted by changing the lipidoid head structure of N-series LNPs.
• lipidoid composition may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the lipidoid composition, and, if desired, another type of therapeutic agent being administered with the lipidoid composition of the invention.
• a larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
• the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
• the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
• “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
• Articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
• alkyl refers to saturated aliphatic groups, including but not limited to C 1 -C 10 straight-chain alkyl groups or C 1 -C 10 branched-chain alkyl groups.
• the "alkyl” group refers to C 1 -C 6 straight-chain alkyl groups or C 1 -C 6 branched- chain alkyl groups.
• the "alkyl” group refers to C 1 -C 4 straight-chain alkyl groups or C 1 -C 4 branched-chain alkyl groups.
• alkyl examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2- pentyl, 3 -pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 1 -heptyl, 2-heptyl, 3 -heptyl, 4- heptyl, 1 -octyl, 2-octyl, 3 -octyl or 4-octyl and the like.
• the "alkyl” group may be optionally substituted.
• acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
• R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
• aminoalkyl refers to an alkyl group substituted with an amino group.
• Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
• ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include "alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
• sulfoxide is art-recognized and refers to the group-S(O)-.
• Embodiment 3 The composition of embodiment 1, wherein the composition is for modifying an expression profile of a target gene or a gene product thereof in the target organ or the target cell
• R b2 , R b3 and R b4 are each independently
• Embodiment 26 The composition of embodiment 25, wherein each m is independently 1 or 2.
• Embodiment 32 The composition of any one of embodiments 1-31, wherein the lipidoid of Formula (I), or the pharmaceutically acceptable salt thereof, is present in the lipid composition at a molar percentage of no more than about 50%.
• Embodiment 33 The composition of any one of embodiments 1-32, wherein the lipidoid of Formula (I), or the pharmaceutically acceptable salt thereof, is present in the lipid composition at a molar percentage of no more than about 40%.
• Embodiment 45 The composition of any one of embodiments 1-44, wherein the pharmaceutical agent comprises a polynucleotide.
• Embodiment 46 The composition of any one of embodiments 1-44, wherein the pharmaceutical agent is a messenger ribonucleic acid (mRNA), an oligonucleotide, a polypeptide, an oligopeptide, a small molecule compound, or any combination thereof.
• mRNA messenger ribonucleic acid
• Embodiment 47 The composition of embodiment 46, wherein the polypeptide is a protein.
• Embodiment 60 The composition of any one of embodiments 54-69, wherein the polynucleotide is a messenger ribonucleic acid (mRNA).
• mRNA messenger ribonucleic acid
• Embodiment 76 The composition of any one of embodiments 71-75, wherein the lipidoid of Formula (I), or the pharmaceutically acceptable salt thereof, is a lipidoid having structural Formula (II A ), (II B ), (lI C ), (II D ), or (II E ):
• Embodiment 87 The composition of any one of embodiments 76-86, wherein, in Formula (II B ), (II D ), or (II E ), m2 is 1 or 2.
• Embodiment 103 The composition of any one of embodiments 71-103, wherein the target gene or gene product thereof is a target protein or a functional variant thereof or a target transcript.
• Embodiment 105 The composition of any one of embodiments 98-104, wherein the pharmaceutical agent is associated with a lung disease or disorder.
• Embodiment 130 The composition of any one of embodiments 119-129, wherein, in Formula (IIIe), (III D ), or (III E ), m7 is 1 or 2.
• Embodiment 143 The composition of embodiment 140 or 141, wherein the pharmaceutical agent encodes or is configured to down-regulate a target gene or a gene product thereof that is specific to or primarily found in the liver or the liver cell.
• Embodiment 150 The method of any one of embodiments 147-149, wherein the non-liver organ is a lung, and wherein the non-liver cell is a lung cell.
• PCR products 400 ng were hybridized in NEBuffer 2 (New England Biolabs) by heating to 95°C for 5 min, followed by a 2 °C / second ramp down to 85 °C and a 0.1 °C / second ramp down to 25 °C on a AppliedBiosystems PCR system (Thermo Fisher Scientific).
• the annealed samples were digested by T7 Endonuclease I (New England Biolabs) at 37 °C for 15 min, followed by incubating at 65 °C for 5 min to stop the reaction.
• the products were further purified and run on a 4-20% Novex TBE gel (Invitrogen).
• the lung solution was filtered through a 70- ⁇ m strainer to proceed to single-cell suspension, centrifuged, and then treated with red blood cell lysis buffer (eBioscience) for 5 min. The solution was then centrifuged again to harvest a cell pellet. Cells were resuspended in flow cytometry staining buffer (eBioscience), and then antibodies were added and incubated for 30 min on ice in the dark. The stained cells were washed twice with cold PBS, resuspended in PBS, and measured using an LSR-II flow cytometer (BD Bioscience).
• the 306-012B LNP was used to deliver the LoxP -targeted sgRNA (sgLoxP) to mice engineered to express both the Ail 4 construct and a constitutively-expressed Cas9 construct (Ail4+/Cas9+ mouse model).
• FiGs. 10 A and 10B show 306-012B LNP enabled sgLoxP-mediated genome editing in Ail4/Cas9 crossing mice.
• delivery of sgLoxP with optimized 306-012B LNP system resulted in red fluorescence detected specifically in the liver.
• further histological analysis as shown in Fig.
• In vivo CRISPR mRNA delivery may result in a genomic knockdown which is durable for at least 1 full year after administration.
• sequencing data indicated durable genomic editing at least to 150 days.
• Disclosed data indicates a very slight reduction in genomic editing efficiency over time, which may reflect the slow turnover of hepatocytes in the liver, which have a predicted life of approximately 300 days.
• the genomic editing efficiency of a 3 mg/kg dose detected at 150 days after injection (31%) is still higher than the editing efficiency of a lower 2 mg/kg dose detected at only 100 days after injection (22%).
• the 22% genome editing rate was sufficient to generate a statistically significant reduction of ANGPTL3 protein, as well as serum cholesterol and LDL-C.
• Example 7 306-N16B LNP enables the delivery of mRNA to the pulmonary endothelial cells
• Phospho-S6 (a marker of TSC2-deficient cells) immunostaining revealed strong co-localization of phospho-S6 and EGFP (Fig. 32C), confirming that hLNP enables specific delivery of EGFP mRNA to TTJ cells.

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• 2022
  • 2022-01-18 AU AU2022208484A patent/AU2022208484A1/en not_active Abandoned
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