WO1997020579A2 - Nouveaux composes et leur utilisation - Google Patents
Nouveaux composes et leur utilisation Download PDFInfo
- Publication number
- WO1997020579A2 WO1997020579A2 PCT/EP1996/005477 EP9605477W WO9720579A2 WO 1997020579 A2 WO1997020579 A2 WO 1997020579A2 EP 9605477 W EP9605477 W EP 9605477W WO 9720579 A2 WO9720579 A2 WO 9720579A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nucleic acid
- conjugate according
- fragment
- neurotoxin
- conjugate
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title description 14
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 27
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 27
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 27
- 239000002581 neurotoxin Substances 0.000 claims abstract description 23
- 231100000618 neurotoxin Toxicity 0.000 claims abstract description 23
- 239000012634 fragment Substances 0.000 claims abstract description 19
- 101710138657 Neurotoxin Proteins 0.000 claims abstract description 17
- 210000000653 nervous system Anatomy 0.000 claims abstract description 9
- 230000001225 therapeutic effect Effects 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 108020004414 DNA Proteins 0.000 claims description 4
- 102000053602 DNA Human genes 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- 230000003000 nontoxic effect Effects 0.000 claims description 4
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- 230000021615 conjugation Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 claims description 2
- 230000027455 binding Effects 0.000 claims description 2
- 230000006337 proteolytic cleavage Effects 0.000 claims description 2
- 230000001580 bacterial effect Effects 0.000 claims 2
- 239000000688 bacterial toxin Substances 0.000 claims 2
- 239000003998 snake venom Substances 0.000 claims 2
- 239000002299 complementary DNA Substances 0.000 claims 1
- 238000010188 recombinant method Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 6
- 239000003053 toxin Substances 0.000 description 6
- 231100000765 toxin Toxicity 0.000 description 6
- 108700012359 toxins Proteins 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 4
- 230000032258 transport Effects 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- LAQCZBYXNRANFU-UIAUUDGKSA-N Crotoxin Natural products CC=C/C(=O)O[C@@H]1C[C@H]2O[C@H]3C=C(C)[C@@H]4O[C@@H]4[C@]3(C)[C@]1(C)[C@]25CO5 LAQCZBYXNRANFU-UIAUUDGKSA-N 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 241000270295 Serpentes Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010043376 Tetanus Diseases 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 150000002605 large molecules Chemical class 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 241001112695 Clostridiales Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 241000270311 Crocodylus niloticus Species 0.000 description 1
- 241000271532 Crotalus Species 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000007441 retrograde transport Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- LYTCVQQGCSNFJU-LKGYBJPKSA-N α-bungarotoxin Chemical compound C(/[C@H]1O[C@H]2C[C@H]3O[C@@H](CC(=C)C=O)C[C@H](O)[C@]3(C)O[C@@H]2C[C@@H]1O[C@@H]1C2)=C/C[C@]1(C)O[C@H]1[C@@]2(C)O[C@]2(C)CC[C@@H]3O[C@@H]4C[C@]5(C)O[C@@H]6C(C)=CC(=O)O[C@H]6C[C@H]5O[C@H]4C[C@@H](C)[C@H]3O[C@H]2C1 LYTCVQQGCSNFJU-LKGYBJPKSA-N 0.000 description 1
Classifications
-
- 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
- A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
Definitions
- the present invention relates to novel therapeutic conjugates and their use in targeting therapeutic substances, in particular nucleic acids, to the central nervous system.
- therapeutic substances in particular nucleic acids
- Large molecules introduced into the body systemically or into peripheral tissues are not transported into the nervous system in therapeutically significant amounts as they are unable to cross the so-called 'blood brain barrier'.
- Hence the direct therapeutic application of large molecules such as nucleic acids is currently not feasible.
- Some neurotoxins have specific properties that allow them to invade the vertebrate nervous system. They bind specifically to the surface of neurons, which are the primary cellular elements of the nervous system. The neurotoxin is internalised, and retrogradely transported by those neurons to the neuronal cell body. The neurotoxin may also be transported transneuronally to second order neurons in the nervous system. In some cases it has been shown that the properties which allow transport ofthe neurotoxin are conferred by a particular fragment of the toxin. Examples of such toxins are clostridial neurotoxins such as those from Tetanus and Botulinum, and snake toxins such as crotoxin and dendrotoxin, from the rattlesnake and mamba snake respectively.
- HRP horse radish peroxidase
- the present invention relates to the use of neurotoxins to transport therapeutically active nucleic acids across the blood brain barrier into the nervous system.
- the present invention provides a novel conjugate comprising a neurotoxin or a fragment thereof and a nucleic acid.
- the conjugate of the invention may also be referred to herein as the compound ofthe invention.
- the neurotoxins employed in the present invention may be any suitable neurotoxin which has the ability to cross the blood-brain barrier.
- the neurotoxin may be derived from bacteria, such as Tetanus or Bolulinum toxin; or from snakes, such as crotoxin or dendrotoxin; or it may be a fragment of such toxins.
- a neurotoxin fragment can be prepared by methods well known in the protein art, for example by proteolytic cleavage or by genetic engineering strategies. Said fragment is preferably a non-toxic binding fragment.
- the nucleic acids may be single or double stranded DNA or RNA molecules, either circular or linear in form, encoding either whole genes, cDNAs, non-coding sequence, genetic control regions, or antisense constructs.
- the nucleic acid preferably exerts a therapeutic effect.
- the conjugation may be chemical in nature using chemical linkers such as poly ⁇ lysine, or covalent linkers.
- Other protein, nucleic acid, or other molecular components may also be part ofthe total conjugate, so as to endow the conjugate with other properties. For example, other components such as haemoglutinin might be included that aid trasport from the lysosomal compartment, or nuclear localisation sequences might aid transport into the nucleus.
- Conjugates according to the present invention may be prepared by conventional methods known in the art.
- conjugates may be introduced into either the somatic (i.e. non-neural) or neural tissue of patients using methods known in the art, typically by hypodermic injection.
- somatic i.e. non-neural
- neural tissue typically by hypodermic injection.
- the conjugate will exert a therapeutic effect.
- the invention therefore further provides a pharmaceutical composition
- a pharmaceutical composition comprising a conjugate ofthe invention and a pharmaceutically acceptable carrier.
- the conjugate will normally be employed in the form of a pharmaceutical composition in association with a human pharmaceutical carrier, diluent and/or excipient, although the exact form ofthe composition will depend on the mode of administration.
- the conjugate may, for example, be employed in the form of an aerosol or nebulisable solution for inhalation or a sterile solution for parenteral administration, intra-articuiar administration or intra-cranial administration.
- the dosage ranges for administration ofthe compounds ofthe present invention are those to produce the desired therapeutic effect.
- Suitable daily dosages are in the range 0.01-l Omg/kg, eg 0.01- 5mg/kg, more particularly 0.02-1.5mg/kg, eg 0.04- 1.5mg/kg.
- the unit dosage can vary from less than lmg to 300mg, but typically will be in the region of 1 to lOOmg eg 1 to 50 mg per dose, which may be administered in one or more doses, such as one to six doses per day, Wide variations in the required dosage, however, are to be expected in view ofthe variety of nucleic acids available and the differing efficiencies of various routes of administration. For example, oral administration would be expected to require higher dosages than administration by intravenous injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization, as is well understood in the art.
- Compositions suitable for injection may be in the form of solutions, suspensions or emulsions, or dry powders which are dissolved or suspended in a suitable vehicle prior to use.
- Fluid unit dosage forms are prepared utilising the compound and a pyrogen-free sterile vehicle.
- the compound depending on the vehicle and concentration used, can be either dissolved or suspended in the vehicle. Solutions may be used for all forms of parenteral administration, and are particularly used for intravenous infection. In preparing solutions the compound can be dissolved in the vehicle, the solution being made isotonic if necessary by addition of sodium chloride and sterilised by filtration through a sterile filter using aseptic techniques before filling into suitable sterile vials or ampoules and sealing. Alternatively, if solution stability is adequate, the solution in its sealed containers may be sterilised by autoclaving. Advantageously additives such as buffering, solubilising, stabilising, preservative or bactericidal, suspending or emulsifying agents and/or local anaesthetic agents may be dissolved in the vehicle.
- Dry powders which are dissolved or suspended in a suitable vehicle prior to use may be prepared by filling pre-sterilised drug substance and other ingredients into a sterile container using aseptic technique in a sterile area.
- the drug and other ingredients may be dissolved in an aqueous vehicle, the solution is sterilised by filtration and distributed into suitable containers using aseptic technique in a sterile area. The product is then freeze dried and the containers are sealed aseptically.
- Parenteral suspensions suitable for intramuscular, subcutaneous or intradermal injection, are prepared in substantially the same manner, except that the sterile compound is suspended in the sterile vehicle, instead of being dissolved and sterilisation cannot be accomplished by filtration.
- the compound may be isolated in a sterile state or alternatively it may be sterilised after isolation, e.g. by gamma irradiation.
- a suspending agent for example polyvinylpyrrolidone is included in the composition to facilitate uniform distribution ofthe compound.
- Compositions suitable for administration via the respiratory tract include aerosols, nebulisable solutions or microfine powders for insufflation.
- compositions may be made up in a conventional manner and employed in conjunction with conventional administration devices.
- a method of treating a condition or disease which is susceptible of treatment with a nucleic acid in a mammal e.g. a human which comprises administering to the sufferer an effective, non-toxic amount of a compound of the invention.
- a condition or disease which is susceptible of treatment with a nucleic acid may be for example a condition or disease which may be treated by or requiring gene therapy.
- the invention further provides a compound ofthe invention for use as an active therapeutic substance, in particular for use in treating a condition or disease which is susceptible of treatment with a nucleic acid eg a condition or disease requiring or treatable by gene therapy.
- the invention also provides the use of a compound of the invention in the manufacture of a medicament for treating a condition or disease which is susceptible of treatment with a nucleic acid eg a condition or disease requiring or treatable by gene therapy.
- the invention also provides the use of a conjugate according to the present invention for the manufacture of a medicament for transporting nucleic acids to the central nervous system.
- the invention also provides a therapeutic delivery system comprising a neurotoxin or a fragment thereof and a nucleic acid.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Toxicology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
On décrit l'utilisation de neurotoxines ou de fragments de celles-ci, pour transporter des acides nucléiques dans le système nerveux, ainsi que l'utilisation de conjugués comprenant une neurotoxine ou un fragment de celle-ci et un acide nucléique.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9524807.6A GB9524807D0 (en) | 1995-12-05 | 1995-12-05 | Novel compounds |
| GB9524807.6 | 1995-12-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1997020579A2 true WO1997020579A2 (fr) | 1997-06-12 |
| WO1997020579A3 WO1997020579A3 (fr) | 1997-09-25 |
Family
ID=10784907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1996/005477 WO1997020579A2 (fr) | 1995-12-05 | 1996-12-02 | Nouveaux composes et leur utilisation |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB9524807D0 (fr) |
| WO (1) | WO1997020579A2 (fr) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000033880A3 (fr) * | 1998-12-04 | 2000-10-12 | Deutsches Krebsforsch | Conjugue pour l'administration dans des cellules neuronales |
| US6306403B1 (en) | 2000-06-14 | 2001-10-23 | Allergan Sales, Inc. | Method for treating parkinson's disease with a botulinum toxin |
| WO2003087368A3 (fr) * | 2002-04-18 | 2004-04-29 | Lynkeus Bio Tech Gmbh | Moyens et procedes pour la modulation specifique de genes cibles dans le snc et l'oeil, et procedes pour leur identification |
| WO2009083738A3 (fr) * | 2007-12-31 | 2009-08-27 | Syntaxin Limited | Véhicules de délivrance d'arn |
| US8470792B2 (en) | 2008-12-04 | 2013-06-25 | Opko Pharmaceuticals, Llc. | Compositions and methods for selective inhibition of VEGF |
| US8541384B2 (en) | 2002-07-24 | 2013-09-24 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of angiogenesis |
| US8609112B2 (en) | 2003-10-29 | 2013-12-17 | Allergan, Inc. | Botulinum toxin treatments of depression |
| US8609113B2 (en) | 2003-10-29 | 2013-12-17 | Allergan, Inc. | Botulinum toxin treatments of depression |
| US8617572B2 (en) | 2003-10-29 | 2013-12-31 | Allergan, Inc. | Botulinum toxin treatments of depression |
| US10064921B2 (en) | 2003-10-29 | 2018-09-04 | Allergan, Inc. | Botulinum toxin treatments of neurological and neuropsychiatric disorders |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8914984D0 (en) * | 1989-06-29 | 1989-08-23 | Animal Health Inst | Nucleotide sequences |
| DE69511860T2 (de) * | 1994-05-31 | 2000-02-10 | Allergan, Inc. | Modifizierung von clostridium-toxinen und ihre anwendung als transport proteine |
| WO1996004001A1 (fr) * | 1994-08-05 | 1996-02-15 | Molecular/Structural Biotechnologies, Inc. | Complexes biomoleculaires diriges |
-
1995
- 1995-12-05 GB GBGB9524807.6A patent/GB9524807D0/en active Pending
-
1996
- 1996-12-02 WO PCT/EP1996/005477 patent/WO1997020579A2/fr active Application Filing
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000033880A3 (fr) * | 1998-12-04 | 2000-10-12 | Deutsches Krebsforsch | Conjugue pour l'administration dans des cellules neuronales |
| US6306403B1 (en) | 2000-06-14 | 2001-10-23 | Allergan Sales, Inc. | Method for treating parkinson's disease with a botulinum toxin |
| US8202845B2 (en) | 2002-04-18 | 2012-06-19 | Acuity Pharmaceuticals, Inc. | Means and methods for the specific modulation of target genes in the CNS and the eye and methods for their identification |
| WO2003087368A3 (fr) * | 2002-04-18 | 2004-04-29 | Lynkeus Bio Tech Gmbh | Moyens et procedes pour la modulation specifique de genes cibles dans le snc et l'oeil, et procedes pour leur identification |
| WO2003087367A3 (fr) * | 2002-04-18 | 2004-04-29 | Lynkeus Biotech Gmbh | Moyens et procedes pour l'inhibition specifique de genes dans les cellules et le tissu du systeme nerveux central et/ou de l'oeil |
| US8946403B2 (en) | 2002-07-24 | 2015-02-03 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of angiogenesis |
| US8541384B2 (en) | 2002-07-24 | 2013-09-24 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of angiogenesis |
| US8546345B2 (en) | 2002-07-24 | 2013-10-01 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of angiogenesis |
| US9150863B2 (en) | 2002-07-24 | 2015-10-06 | The Trustees Of The University Of Pennsylvania | Compositions and methods for siRNA inhibition of angiogenesis |
| US8609112B2 (en) | 2003-10-29 | 2013-12-17 | Allergan, Inc. | Botulinum toxin treatments of depression |
| US8609113B2 (en) | 2003-10-29 | 2013-12-17 | Allergan, Inc. | Botulinum toxin treatments of depression |
| US8617572B2 (en) | 2003-10-29 | 2013-12-31 | Allergan, Inc. | Botulinum toxin treatments of depression |
| US9238061B2 (en) | 2003-10-29 | 2016-01-19 | Allergan, Inc. | Botulinum toxin treatment of anxiety and bipolar disorders |
| US10064921B2 (en) | 2003-10-29 | 2018-09-04 | Allergan, Inc. | Botulinum toxin treatments of neurological and neuropsychiatric disorders |
| WO2009083738A3 (fr) * | 2007-12-31 | 2009-08-27 | Syntaxin Limited | Véhicules de délivrance d'arn |
| US8470792B2 (en) | 2008-12-04 | 2013-06-25 | Opko Pharmaceuticals, Llc. | Compositions and methods for selective inhibition of VEGF |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9524807D0 (en) | 1996-02-07 |
| WO1997020579A3 (fr) | 1997-09-25 |
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