CA2186118A1 - Compacted nucleic acids and their delivery to cells - Google Patents

Compacted nucleic acids and their delivery to cells

Info

Publication number
CA2186118A1
CA2186118A1 CA002186118A CA2186118A CA2186118A1 CA 2186118 A1 CA2186118 A1 CA 2186118A1 CA 002186118 A CA002186118 A CA 002186118A CA 2186118 A CA2186118 A CA 2186118A CA 2186118 A1 CA2186118 A1 CA 2186118A1
Authority
CA
Canada
Prior art keywords
nucleic acid
composition
binding moiety
complex
target cell
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.)
Granted
Application number
CA002186118A
Other languages
French (fr)
Other versions
CA2186118C (en
Inventor
Richard W. Hanson
Jose C. Perales
Thomas W. Ferkol, Jr.
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.)
Ohio University
Case Western Reserve University
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of CA2186118A1 publication Critical patent/CA2186118A1/en
Application granted granted Critical
Publication of CA2186118C publication Critical patent/CA2186118C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic 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
    • A61K47/50—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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • 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
    • A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • 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)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/644—Coagulation factor IXa (3.4.21.22)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21022—Coagulation factor IXa (3.4.21.22)
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Abstract

Nucleic acids are compared, substantially without aggregation, to facilitate their uptake by target cells of an organism to which the compacted material is administered. The nucleic acids may achieve a clinical effet as a result of gene expression, hybridization to endogenous nucleic acids whose expression is undesired, or site-specific integration so that a target gene is replaced, modified or deleted. The targeting may be enhanced by means of a target cell-binding moiety. The nucleic acid is preferably compacted to a condensed state.

Claims (48)

1.Use of unaggregated nucleic acid complexes, each consisting essentially of a single nucleic acid molecule and one or more carrier molecule, said carrier molecule having a nucleic acid binding moiety through which it is complexed to the nucleic acid, said complex being compacted to a diameter of less than 90 nm, in the manufacture of a composition for the prevention or treatment of a disease or other clinical condition in a subject as a result of the integration, hybridization or expression of said nucleic acid within target cells of said subject.
2.A composition comprising unaggregated nucleic acid complexes, each complex consisting essentially of a single nucleic acid molecule and one or more carrier molecules, said carrier molecule having a nucleic acid binding moiety through which it is complexed to the nucleic acid, and a target cell-binding moiety through which it may bind to a target cell and whereby said complex may more readily enter the target cell. said complex being compacted to a diameter of less than 90 nm.
3.The use of claim 1 or composition of claim 2 wherein the DNA
complex is condensed to a diameter less than 30 nm.
4.The use of claim 1 or composition of claim 2 wherein the DNA
complex is condensed to a diameter less than 23 nm.
5.The use of claim 1 or composition of claim 2 wherein the DNA
complex is condensed to a diameter not more than 12 nm.
6.The composition of any of claims 2-5 wherein the target cell binding moiety is an antibody or a specific binding fragment of an antibody.
7.The composition of claim 6 in which the antibody specifically binds the polymeric immunoglobulin receptor.
8.The composition of claim 6 in which the antibody specifically binds CD4 or gp120.
9.The composition of claim 5 wherein the target cell binding moiety is a lectin, or a carbohydrate.
10.The composition of claim 9 wherein the carbohydrate is selected from the group consisting of galactose, lactose, mannose and mannose-6-phosphate.
11.The composition of any of claims 2-5 wherein the target cell binding moiety is a peptide or protein.
12.The composition of claim 11 wherein the target cell binding moiety is selected from the group consisting of insulin, epidermal growth factor, tumor necrosis factor, prolactin, chorionic gonadotropin, follicle stimulating hormone, luteinizing hormone, glucagon, lactoferrin, transferrin, apolipoprotein E, gp120 and albumin.
13.The composition of any of claims 1-12 or use of any of claims 1, 3-5 in which the nucleic acid binding moiety is an antibody or a specific binding fragment of an antibody.
14.The use of any of claims 1, 3-5 or composition of any of claims 2-12 in which the nucleic acid binding moiety is a polycation.
15.The use of any of claims 1, 3-5 or composition of claim 14 in which the polycation is polylysine.
16.The use of any of claims 1, 3-5 or composition of any of claims 2-15 in which the nucleic acid is DNA.
17.The use of any of claims 1, 3-5 or compositions of any of claims 2-15 in which the nucleic acid is RNA.
18.The use of any of claims 1, 3-5 or compositions of any of claims 2-15 in which the nucleic acid is an analogue of DNA or RNA
which is more resistant to degradation in vivo.
19.The use of any of claims 1, 3-5 or compositions of any of claims 2-15 in which the nucleic acid is an analogue of DNA or RNA
which more readily diffuses through cell membranes.
20.The use of any of claims 1, 3-5 or compositions of any of claims 2-15 in which the nucleic acid is an analogue of DNA in which the methylphosphonate analogue of the naturally occurring mononucleotide appears.
21.The use of any of claims 1, 3-5 or compositions of any of claims 2-20 wherein the nucleic acid comprises an expressible gene which is functional in a target cell to which said target cell binding moiety binds.
22.The use of any of claims 1, 3-5 or compositions of claim 21 in which the gene encodes a protein selected from the group consisting of enzymes which in mutated form are associated with specific metabolic defects, receptors, toxins, ion channels membrane transporters, and cytoskeletal proteins.
23.The use of any of claims 1, 3-5 or compositions of any of claims 2-22 wherein the nucleic acid comprises sequences homologous to genetic material of the target cell, whereby it may insert itself into the genome thereof by homologous recombination.
24.The use of any of claims 1, 3-5 or compositions of any of claims 2-22 in which the nucleic acid molecule is "antisense" to a target nucleic acid sequence of the target cell, or of a virus which can infect the target cell, whereby it may hybridize sufficiently thereto to inhibit transcription or translation of the target nucleic acid sequence.
25.A method of preparing a composition according to any of claims 2-24 which comprises mixing the nucleic acid with the carrier at a chaotropic salt concentration sufficient for compaction of the complex to a diameter of less than 90 nm.
26.The method of claim 25 in which the mixing is monitored to detect, and prevent or correct, the formation of aggregated or relaxed complexes.
27.The method of claim 25 wherein the salt is NaCl.
28.The method of claim 27 wherein the nucleic acid and the carrier are each, at the time of mixing, in a solution having a salt concentration of 0.05 to 1.5 M.
29.The method of claim 25 in which the DNA binding moiety is a polycation and the molar ratio of the phosphate groups of the nucleic acid to the positively charged groups of the polycation is in the range of 4:1 to 1:4.
30.The method of claim 29 in which the polycation is added slowly to the nucleic acid, while vortexing at high speed.
31.The method of claim 25 wherein the mixing is monitored by a method selected form the group consisting of electron microscopy, circular dichroism, and absorbance measurement.
32.Use of a composition according to any of claims 2-24 in the manufacture of a composition for the prevention or treatment of a disease or other undesired clinical condition in a human or nonhuman animal subject as a result of the integration, hybridization of said nucleic acid within target cells of said subject.
33.The use of claims 1 or 32 in which the composition is injected into a tissue of the subject.
34.The use of claim 32 wherein the composition is directed to particular target cells by means of a target cell-binding moiety in accordance with claim 5.
35.The use of claim 1 wherein the carrier lacks a target cell-binding moiety other than said nucleic acid-binding moiety.
36.The use of claims 1 or 32 wherein the disease or other clinical condition is prevented or treated as a result of gene expression.
37.The use of claims 1 or 32 wherein the disease or other clinical condition is prevented or treated as a result of hybridization.
38.The composition of any of claims 2-24 wherein the nucleic acid is encapsulated in a liposome.
39.The use of any of claims 1 and 32-37 wherein the composition is according to claim 38.
40. The use of claim 1 wherein said complex is compacted to a diameter which is less than (a) double the theoretical diameter of a complex of single DNA molecule and a sufficient number of carrier molecules to provide a charge ratio of 1:1 in the form of a condensed sphere, and (b) 30nm, whichever is larger.
41. The composition of claim 2 wherein said complex is compacted to a diameter which is less than (a) double the theoretical diameter of a complex of single DNA molecule and a sufficient number of carrier molecules to provide a charge ratio of 1:1 in the form of a condensed sphere, and (b) 30nm, whichever is larger.
42. A method of preparing a complex according to any of claims 1-24 which comprises mixing the nucleic acid with the carrier at a chaotropic salt concentration sufficient for compaction of the complex to a diameter of less than 90 nm.
43. The method of claim 42 in which the mixing is monitored to detect, and prevent or correct, the formation of aggregated or relaxed complexes.
44. The method of claim 42 wherein the salt is NaCl.
45. The method of claim 44 wherein the nucleic acid and the carrier are each, at the time of mixing, in a solution having a salt concentration of 0-.05 to 1.5 M.
46. The method of claim 42 in which the DNA binding moiety is a polycation and the molar ratio of the phosphate groups of the nucleic acid to the positively charged groups of the polycation is in the range of 4:1 to 1:4.
47. The method of claim 46 in which the polycation is added slowly to the nucleic acid, while vortexing at high speed.
48. The method of claim 42 wherein the mixing is monitored by electronic microscopy, circular dichroism, or absorbance measurements, or a combination thereof
CA2186118A 1994-03-23 1995-03-23 Compacted nucleic acids and their delivery to cells Expired - Fee Related CA2186118C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21653494A 1994-03-23 1994-03-23
US08/216,534 1994-03-23
PCT/US1995/003677 WO1995025809A1 (en) 1994-03-23 1995-03-23 Compacted nucleic acids and their delivery to cells

Publications (2)

Publication Number Publication Date
CA2186118A1 true CA2186118A1 (en) 1995-09-28
CA2186118C CA2186118C (en) 2010-10-19

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Family Applications (1)

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CA2186118A Expired - Fee Related CA2186118C (en) 1994-03-23 1995-03-23 Compacted nucleic acids and their delivery to cells

Country Status (9)

Country Link
US (3) US5877302A (en)
EP (1) EP0752005B1 (en)
JP (2) JP4285766B2 (en)
AT (1) ATE410518T1 (en)
AU (1) AU696455C (en)
CA (1) CA2186118C (en)
DE (1) DE69535853D1 (en)
ES (1) ES2316148T3 (en)
WO (1) WO1995025809A1 (en)

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