ES2536791T3 - Administración de vectores lentivirales al cerebro - Google Patents

Administración de vectores lentivirales al cerebro Download PDF

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ES2536791T3
ES2536791T3 ES11727743.4T ES11727743T ES2536791T3 ES 2536791 T3 ES2536791 T3 ES 2536791T3 ES 11727743 T ES11727743 T ES 11727743T ES 2536791 T3 ES2536791 T3 ES 2536791T3
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vev
protein
administration
vector
brain
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Peter Widdowson
Scott Ralph
Kyriacos Mitrophanous
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Oxford Biomedica UK Ltd
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Oxford Biomedica UK Ltd
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • 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
    • A61K48/0075—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 delivery route, e.g. oral, subcutaneous
    • 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
    • A61K48/0083—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 administration regime
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • 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
    • A61K48/005—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 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Hospice & Palliative Care (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Un vector lentiviral para la administración al putamen para su uso en el tratamiento de una afección neurológica, en el que una composición que comprende el vector lentiviral se administra directamente al putamen por infusión continua usando una cánula y en el que se administran entre 10-600 &mul de la composición de vector por tramo a una velocidad de flujo de al menos 2 μl/min, y en el que el vector lentiviral se administra usando una cánula con una perforación equivalente o más estrecha de aproximadamente 28 de calibre.

Description

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CD4. Pero si el gen env en estos vectores se ha sustituido con secuencias de env de otros virus de ARN, entonces puede tener un espectro infeccioso más amplio (Verma y Somia (1997) Nature 389(6648):239-242). A modo de ejemplo, Miller et al. pseudotiparon un vector MoMLV con la envuelta del retrovirus anfotrópico 4070A (Mol. Cell. Biol. 5:431-437), otros colaboradores han pseudotipado un vector lentiviral basado en el VIH con la glucoproteína del VEV (Verma y Somia (1997) Nature 389(6648):239-242).
En otra alternativa, la proteína Env puede ser una proteína Env modificada tal como una proteína Env mutante o manipulada. Las modificaciones pueden hacerse o seleccionarse para introducir la capacidad de elección de diana o para reducir la toxicidad o para otro fin (Marin et al. (1996) J Virol 70(5):2957-2962; Nilson et al. (1996) Gene Ther 3(4):280-286; y Fielding et al. (1998) Blood 91(5):1802-1809 y referencias citadas en su interior).
El vector puede pseudotiparse, por ejemplo, con un gen que codifica al menos parte de la proteína G de la rabia o la proteína VEV-G.
VEV-G:
La proteína de la envuelta (G) del virus de la estomatitis vesicular (VEV), un rabdovirus, es una proteína de la envuelta que se ha mostrado que es capaz de pseudotipar ciertos retrovirus que incluyen lentivirus.
Su capacidad para pseudotipar vectores retrovirales basados en MoMLV en ausencia de cualquier retroproteína de la envuelta vírica se mostró por primera vez por Emi y col. (1991) J. Virol. 65:1202-1207. El documento WO 94/294440 enseña que los vectores retrovirales pueden pseudotiparse satisfactoriamente con VEV-G. Estos vectores de VEV-G pseudotipados pueden usarse para transducir una amplia variedad de células de mamífero. Más recientemente, Abe et al. (1998) J. Virol 72(8): 6356-6361 enseñan que las partículas retrovirales no infecciosas pueden hacerse infecciosas mediante la adición de VEV-G.
Burns et al. (1993) Proc. Natl. Acad. Sci. USA 90:8033-8037 pseudotiparon satisfactoriamente el retrovirus VLM con VEV-G y esto produjo un vector que tenía un intervalo de huéspedes alterado en comparación con el VLM en su forma nativa. Se ha mostrado que los vectores pseudotipados con VEV-G infectan no solo células de mamífero, sino también líneas celulares derivadas de peces, reptiles e insectos (Burns et al. (1993) Proc. Natl. Acad. Sci. USA 90:8033-8037). También han mostrado que es más eficaz que las envueltas anfotrópicas tradicionales para una variedad de líneas celulares (Yee y col. (1994) Proc. Natl. Acad. Sci. USA 91:9564-9568 y Emi et al. (1991) J. Virol. 65:1202-1207). La proteína del VEV-G también puede usarse para pseudotipar ciertos lentivirus y retrovirus debido a que su cola citoplásmica puede interaccionar con los núcleos retrovirales.
La provisión de una envuelta de pseudotipado no lentiviral tal como la proteína VEV-G proporciona la ventaja de que las partículas de vector pueden concentrarse a un alto título sin pérdida de infectividad (Akkina et al. (1996) J. Virol. 70:2581-2585). Las proteínas de la envuelta de lentivirus y retrovirus son evidentemente incapaces de resistir a las fuerzas de cizallamiento durante la ultracentrifugación, probablemente debido a que consisten en dos subunidades no covalentemente ligadas. La interacción entre las subunidades puede romperse por la centrifugación. En comparación, la glucoproteína del VEV está compuesta por una única unidad. Por tanto, el pseudotipado de la proteína del VEV-G puede ofrecer posibles ventajas.
El documento WO 00/52188 describe la generación de vectores retrovirales y lentivirales pseudotipados, de líneas celulares productoras estables, que tienen la proteína G del virus de la estomatitis vesicular (VEV-G) como proteína de la envuelta viral asociada a la membrana, y proporciona una secuencia de gen para la proteína del VEV-G.
Virus del río Ross
Se ha usado la envuelta viral del río Ross para pseudotipar un vector lentiviral no de primate (VIF) y tras la administración sistémica transdujo predominantemente el hígado (Kang et al. (2002) J Virol 76(18):9378-9388). Se informó que la eficiencia era 20 veces superior a la obtenida con el vector pseudotipado por VEV-G, y provocó menos citotoxicidad como se mide por niveles en suero de enzimas del hígado sugerentes de hepatotoxicidad.
El virus del río Ross (VRR) es un alfavirus propagado por mosquitos que es endémico y epidémico en regiones tropicales y templadas de Australia. Las tasas de anticuerpo en las poblaciones normales en la zona costera templada tienden a ser bajas (6 % al 15 %), aunque la sero-prevalencia alcanza del 27 al 37 % en las planicies del sistema del río del valle de Murray. De 1979 a 1980, el virus del río Ross se volvió endémico en las islas del Pacífico. La enfermedad no es contagiosa entre seres humanos y nunca es mortal, siendo el primer síntoma el dolor de articulaciones con fatiga y letargo en aproximadamente la mitad de los pacientes (Fields Virology, quinta edición (2007) Eds. Knipe y Howley. Lippincott Williams and Wilkins).
Baculovirus GP64
Se ha mostrado que la proteína del baculovirus GP64 es una alternativa atractiva a VEV-G para vectores virales usados en la producción a gran escala del virus de título alto requerido para aplicaciones clínicas y comerciales
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Claims (1)

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ES11727743.4T 2010-05-28 2011-05-27 Administración de vectores lentivirales al cerebro Active ES2536791T3 (es)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB201009052 2010-05-28
GBGB1009052.0A GB201009052D0 (en) 2010-05-28 2010-05-28 Vector
GB201100502 2011-01-12
GBGB1100502.2A GB201100502D0 (en) 2011-01-12 2011-01-12 Vector
GB201107184 2011-04-28
GBGB1107184.2A GB201107184D0 (en) 2011-04-28 2011-04-28 Vector
PCT/GB2011/051009 WO2011148194A1 (en) 2010-05-28 2011-05-27 Delivery of lentiviral vectors to the brain

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EP (1) EP2575894B1 (es)
JP (1) JP5965392B2 (es)
CN (1) CN102946907A (es)
DK (1) DK2575894T3 (es)
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