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WO1997020579A2 - Novel compounds and use - Google Patents

Novel compounds and use Download PDF

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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
Application number
PCT/EP1996/005477
Other languages
French (fr)
Other versions
WO1997020579A3 (en
Inventor
Jack Price
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of WO1997020579A2 publication Critical patent/WO1997020579A2/en
Publication of WO1997020579A3 publication Critical patent/WO1997020579A3/en

Links

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.

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  • 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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Use of neurotoxins or fragments thereof to transport nucleic acids into the nervous system and conjugates comprising a neurotoxin or a fragment thereof and a nucleic acid.

Description

NOVEL COMPOUNDS AND USE
The present invention relates to novel therapeutic conjugates and their use in targeting therapeutic substances, in particular nucleic acids, to the central nervous system. 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.
The transport properties of neurotoxins have been utilized to target proteins to the nervous system, by conjugating or otherwise linking the toxin or toxin fragment to such molecules, for example the enzyme horse radish peroxidase (HRP) (PS Fishman et al., J. Neurol. Sci., 1990, 98: 311-325), and wheat germ agglutinin.
In one aspect the present invention relates to the use of neurotoxins to transport therapeutically active nucleic acids across the blood brain barrier into the nervous system. In a further aspect 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. Thus for example 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.
Such 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. By the specific binding, internalisation, and retrograde transport ofthe conjugate into the nervous system, the conjugate will exert a therapeutic effect.
The invention therefore further provides a pharmaceutical composition comprising a conjugate ofthe invention and a pharmaceutically acceptable carrier.
In use 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. It will be appreciated that the dosage range required depends on the choice of nucleic acid, the precise nature ofthe conjugate, the route of administration, the nature ofthe formulation, the age ofthe patient, the nature, extent or severity ofthe patient's condition, contraindications, if any, and the judgment of the attending physician. 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.
- 9 . 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. Alternatively 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. Advantageously, 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. In the latter case, particle size of less than 50 microns, especially less than 10 microns, is preferred. Such compositions may be made up in a conventional manner and employed in conjunction with conventional administration devices. In a further aspect there is provided 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.
In a further aspect 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.
No unexpected toxicological effects are expected when compounds ofthe invention are administered in accordance with the present invention.

Claims

1. Use of a neurotoxin or a fragment thereof to transport a nucleic acid into the nervous system.
2. Use according to claim 1 wherein the nucleic acid exerts a therapeutic effect.
3. Use accoding to claim 1 or claim 2 wherein the neurotoxin is selected from a bacterial or snake toxin or a fragment thereof.
4. Use acording to any of claims 1 to 3 wherein the neurotoxin fragment is a non-toxic binding fragment.
5. A conjugate comprising a neurotoxin or a fragment thereof and a nucleic acid.
6. A conjugate according to claim 5 wherein the neurotoxin is selected from a bacterial or snake toxin or a fragment thereof.
7. A conjugate according to claim 5 or 6 wherein the neurotoxin fragment is obtained by proteolytic cleavage.
8. A conjugate according to claim 5 or 6 wherein the neurotoxin fragment is obtained by a recombinant method.
9. A conjugate according to any of claims 5 to 8 wherein the nucleic acid is a single or double stranded DNA or RNA molecule.
10. A conjugate according to claim 9 wherein the nucleic acid encodes a whole gene.
1 1. A conjugate according to claim 9 wherein the nucleic acid encodes a cDNA.
12. A conjugate according to any of claims 5 to 1 1 wherein conjugation is effected by a chemical linker.
13. A conjugate according to any of claims 5 to 1 1 wherein conjugation is effected by a covalent linker.
14. A pharmaceutical composition comprising a conjugate according to any of claims 5 to 13 and a pharmaceutically acceptable carrier therefor.
15. A conjugate ofthe invention for use as an active therapeutic substance.
16. A method of treating a condition or disease which is susceptible of treatment with a nucleic acid in a mammal which method comprises administering to the sufferer an effective, non-toxic amount of a conjugate according to the invention.
17. Use of a conjugate according to the invention in the manufacture of a medicament for treating a a condition or disease which is susceptible of treatment with a nucleic acid.
18. Use of a conjugate according to the invention in the manufacture of a medicament for transporting a nucleic acid to the central nervous system.
19. A therapeutic delivery system comprising a neurotoxin or a fragment thereof and a nucleic acid.
PCT/EP1996/005477 1995-12-05 1996-12-02 Novel compounds and use WO1997020579A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9524807.6 1995-12-05
GBGB9524807.6A GB9524807D0 (en) 1995-12-05 1995-12-05 Novel compounds

Publications (2)

Publication Number Publication Date
WO1997020579A2 true WO1997020579A2 (en) 1997-06-12
WO1997020579A3 WO1997020579A3 (en) 1997-09-25

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/005477 WO1997020579A2 (en) 1995-12-05 1996-12-02 Novel compounds and use

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GB (1) GB9524807D0 (en)
WO (1) WO1997020579A2 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000033880A3 (en) * 1998-12-04 2000-10-12 Deutsches Krebsforsch Conjugate used for enriching in neuronal cells
US6306403B1 (en) 2000-06-14 2001-10-23 Allergan Sales, Inc. Method for treating parkinson's disease with a botulinum toxin
WO2003087367A3 (en) * 2002-04-18 2004-04-29 Lynkeus Biotech Gmbh Means and methods for the specific inhibition of genes in cells and tissue of the cns and/or eye
WO2009083738A3 (en) * 2007-12-31 2009-08-27 Syntaxin Limited Rna delivery vehicles
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8914984D0 (en) * 1989-06-29 1989-08-23 Animal Health Inst Nucleotide sequences
US6203794B1 (en) * 1994-05-31 2001-03-20 Allergan Sales, Inc. Modification of clostridial toxins for use as transport proteins
WO1996004001A1 (en) * 1994-08-05 1996-02-15 Molecular/Structural Biotechnologies, Inc. Site-specific biomolecular complexes

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000033880A3 (en) * 1998-12-04 2000-10-12 Deutsches Krebsforsch Conjugate used for enriching in neuronal cells
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
WO2003087367A3 (en) * 2002-04-18 2004-04-29 Lynkeus Biotech Gmbh Means and methods for the specific inhibition of genes in cells and tissue of the cns and/or eye
WO2003087368A3 (en) * 2002-04-18 2004-04-29 Lynkeus Bio Tech Gmbh Means and methods for the specific modulation of target genes in the cns and the eye and methods for their identification
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 (en) * 2007-12-31 2009-08-27 Syntaxin Limited Rna delivery vehicles
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 (en) 1997-09-25

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