Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2001-11-08
2004-10-05
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093100, C424S093600, C435S320100
Reexamination Certificate
active
06800281
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a vector system, such as a lentiviral vector system for the treatment of neurodegenerative disease in a mammal, e.g., Parkinson's disease.
Further, the present invention relates to a method for treating a neurodegenerative disease and/or symptoms thereof and/or preventing neurodegenerative disease and/or symptoms thereof, in a mammal, comprising, administering a lentiviral vector to a target cell in the brain or nervous system of the mammal, said lentiviral vector comprising a nucleic acid sequence comprising a sequence encoding a growth factor, advantageously in operable linkage with or operably linked to a promoter sequence, wherein said growth factor is expressed in the target cell, thereby treating said neurodegenerative disease. Advantageously the lentiviral vector is primate or non-primate lentiviral vector such as an EIAV vector or an HIV vector or an SIV vector or an FIV vector. Also advantageously, the growth factor is a GDNF, such as a human GDNF. The GDNF can be modified and the nucleic acid molecule encoding the GDNF can likewise be modified; for instance due to the degeneracy of codon usage, the GDNF coding sequence can be modified, and truncated forms of GDNF can be used, such as those which may be found in the literature. Likewise, analogs, homologs, derivatives, and variants of the GDNF coding sequence can be used and ergo of analogs, homologs, derivatives and variants of GDNF can be expressed; advantageously such expressed analogs, homologs, derivatives and variants of GDNF have activity analogous to that of full length human GDNF, e.g., as employed in the exemplified embodiment herein, and the analogs, homologs, derivatives and variants of the GDNF coding sequence encode such active GDNF analogs, homologs, derivatives, and variants. The mammal is advantageously a primate, such as a human. The administration can be by stereotaxic injection. The administration can be intracranially, e.g., intracranially to stiatum or to substantia nigra. The administration can also be by retrograde transport. The neurodegenerative disease can be Parkinson's disease. The treating of Parkinson's disease can be by prevention of nigrostriatal degeneration and/or induction of nigrostriatal regeneration and/or reversal of motor deficits. And, the growth factor expression can be for up to 8 months.
Even further still, the lentiviral vector can include additional nucleic sequences, such as nucleic acid sequences encoding one or more other members of the GDNF-family of neurotrophic factors, e.g., neurturin, persphin, neublastin, artemin; and/or the lentiviral vector can contain one or more other nucleotide sequences encoding expression products suitable for treating a neurdegenerative disorder, such as Tyrosine Hydroxylase, GTP-cyclohydrolase I, Aromatic Amino Acid Dopa Decarboxylase and Vesicular Monoamine Transporter 2 (VMAT2), preferably nucleic acid sequences encoding Tyrosine Hydroxylase, GTP-cyclohydrolase I and optionally Aromatic Amino Acid Dopa Decarboxylase or Aromatic Amino Acid Dopa Decarboxylase and Vesicular Monoamine Transporter 2. These other nucleotide sequences may also encode proteins such as growth factors, e.g., NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor), and antibodies.
Additionally or alternatively, the lentiviral vector encoding the growth factor, e.g., GDNF, can be administered with one or more additional vectors containing one or more additional nucleic acid sequences, such as nucleic acid sequences encoding one or more other members of the GDNF-family of neurotrophic factors, e.g., neurturin, persphin, neublastin, artemin, and/or other nucleotide sequences encoding expression products suitable for treating a neurdegenerative disorder, such as Tyrosine Hydroxylase, GTP-cyclohydrolase I, Aromatic Amino Acid Dopa Decarboxylase and Vesicular Monoamine Transporter 2 (VMAT2), preferably encoding Tyrosine Hydroxylase, GTP-cyclohydrolase I and optionally Aromatic Amino Acid Dopa Decarboxylase or Aromatic Amino Acid Dopa Decarboxylase and Vesicular Monoamine Transporter 2. These other nucleotide sequences may also encode proteins such as growth factors and antibodies. The one or more additional vector can be any suitable vector such as an adenovirus or lentiviral vector; and, it is presently preferred and considered advantageous that the additional vector be a lentiviral vector, as AAV and adenovirus systems, as herein further discussed, do not obtain the enhanced effects observed with the lentiviral-growth factor, e.g., lentiviral-GDNF of the present invention. “Administration with” the lentiviral vector encoding the growth factor, e.g., GDNF, can be through simultaneous administration, e.g., the vectors are admixed in a single formulation that is administered, or via sequential or concomitant administration of the vectors or formulations containing the vectors.
When a vector genome such as a lentiviral or retroviral vector genome comprises two or more nucleic acid sequences (also known as nucleotide sequences of interest or NOIs), it is advantageous that they are operably linked by one or more Internal Ribosome Entry Site(s), e.g., a genome, advantageously a lentiviral genome, comprising three or more NOIs operably linked by two or more Internal Ribosome Entry Site(s) wherein preferably each NOI is useful in the treatment of a neurodegenerative disorder and at least one of the NOIs is a growth factor such as GDNF.
The invention also relates to vector systems, advantageously lentiviral vector systems, used in the methods of the invention, such as a lentiviral vector system which is capable of delivering an RNA genome to a recipient cell, wherein the genome is longer than the wild type genome of the lentivirus, e.g., an EIAV vector system.
According to further aspects of the invention relates to:
a method for producing a lentiviral particle which comprises introducing such a viral genome into a producer cell;
a viral particle produced by such a system or method;
a pharmaceutical composition comprising such a genome, system or particle;
the use of such a genome, system or particle in the manufacture of a pharmaceutical composition to treat and/or prevent a disease;
a cell which has been transduced with such a system;
a method of treating and/or preventing a disease by using such a genome, system, viral particle or cell;
Thus, the invention relates to pharmaceutical compositions comprising the lentiviral vector or the lentiviral vector and other vector(s) employed in the methods of the invention, as well as kits for preparing such compositions (e.g., the lentiviral vector or the lentiviral vector and the other vector(s) in one or more containers and pharmaceutically acceptable excipient, carrier, diluent, adjuvant, and the like in one or more additional containers, wherein said containers can be provided in one or more packages, for instance, packaged together or separately, and optionally including instructions for admixture and/or administration).
The invention can also relate to a bicistronic cassette comprising a nucleotide sequence capable of encoding the growth factor, e.g., GDNF, and an additional nucleic acid sequence, e.g., an additional nucleic acid sequences encoding one or more other GDNF-family of neurotrophic factors or useful in treating or preventing neurodegenerative disease, such as those above-mentioned or otherwise mentioned herein or in documents incorporated by reference herein, operably linked by one or more IRES(s). The invention likewise can also relate to tricistronic cassettes comprising a nucleotide sequence capable of encoding the growth factor, e.g., GDNF, and a first additional nucleic acid sequence, e.g., an additional nucleic acid sequences encoding one or more other GDNF-family of neurotrophic factors or useful in treating or preventing neurodegenerative disease, such as those above-mentioned or otherwise mentioned herein or in documents incorporated by reference herein and a second additional nucleic acid sequence, e.g., an additional nuc
Aebischer Patrick
Kingsman Susan Mary
Mazarakis Nicholas
Naylor Stuart
Frommer Lawrence & Haug
Guzo David
Kowalski Thomas J.
Oxford Biomedica (UK) Limited
Yvon Anne-Marie
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