US2012039991A1PendingUtilityA1

Use of apoptosis inhibiting compounds in degenerative neurological disorders

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Assignee: KAPLITT MICHAELPriority: Oct 22, 2004Filed: Aug 17, 2011Published: Feb 16, 2012
Est. expiryOct 22, 2024(expired)· nominal 20-yr term from priority
Inventors:Michael KaplittSerguei Moussatov
C12N 9/93C12N 2800/107C12N 15/86C12N 2750/14111A61K 48/00A61P 25/00A61P 25/28C07K 14/4747A61P 25/16C12N 2830/15C07K 2319/02C12N 2830/48C12N 2750/14143
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Claims

Abstract

The invention provides methods and compositions for localized delivery of a vector comprising a therapeutic agent to a specific region of the brain associated with a neurodegenerative diseases that is characterized by an excess buildup of buildup of intracellular protein aggregates. In particular, the invention provides methods and compositions used to deliver an adeno-associated virus vector (AAV) comprising a nucleotide sequence encoding an inhibitor of apoptosis protein (IAP) to cells in the region.

Claims

exact text as granted — not AI-modified
1 . A method for treating a neurodegenerative disease in a subject comprising: identifying a target site in the central nervous system that requires modification; and
 delivering a composition comprising a nucleotide sequence encoding X-linked inhibitor of apoptosis protein (XIAP), or a peptide fragment thereof, and a pharmaceutically acceptable carrier, wherein the composition is delivered to the target site in the central nervous system to treat or reduce the neurodegenerative disease.   
     
     
         2 . The method of  claim 1 , wherein the XIAP fragment is a 449 amino acid protein. 
     
     
         3 . The method of  claim 1 , wherein the neurodegenerative disease is associated with protein aggregates. 
     
     
         4 . The method of  claim 3 , wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, and Amyloid Lateral Schlerosis (ALS). 
     
     
         5 .- 13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the composition is delivered using stereotaxic delivery. 
     
     
         15 . The method of  claim 1 , wherein the target site in the central nervous system is a region of the brain. 
     
     
         16 . The method of  claim 15 , wherein the region of the brain is selected from the group consisting of basal ganglia, subthalmic nucleus (STN), pedunculopontine nucleus (PPN), substantia nigra (SN), thalamus, hippocampus, cortex, and combinations thereof. 
     
     
         17 . The method of  claim 15 , wherein the region of brain is the substantia nigra pars compacta. 
     
     
         18 .- 39 . (canceled) 
     
     
         40 . A method for treating a neurodegenerative disease in a subject comprising:
 identifying a target site in the central nervous system that requires modification;   delivering a nucleotide sequence encoding an amino acid fragment of X-linked inhibitor of apoptosis protein (XIAP) to the target site in the central nervous system; and   expressing the XIAP in the target site to treat or reduce the neurodegenerative disease.   
     
     
         41 . The method of  claim 40 , wherein the XIAP fragment is a 449 amino acid protein of SEQ ID No. 8. 
     
     
         42 . The method of  claim 40 , wherein the neurodegenerative disease is associated with protein aggregates. 
     
     
         43 . The method of  claim 42 , wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, and Amyloid Lateral Schlerosis (ALS). 
     
     
         44 .- 45 . (canceled) 
     
     
         46 . The method of  claim 40 , wherein the nucleotide sequence is delivered using a liposome-mediated delivery vector. 
     
     
         47 . The method of  claim 40 , wherein the nucleotide sequence vermis delivered using stereotaxic delivery. 
     
     
         48 . The method of  claim 40 , wherein the target site in the central nervous system is a region of the brain. 
     
     
         49 . The method of  claim 48 , wherein the region of the brain is selected from the group consisting of basal ganglia, subthalmic nucleus (STN), pedunculopontine nucleus (PPN), substantia nigra (SN), thalamus, hippocampus, cortex, and combinations thereof. 
     
     
         50 . The method of  claim 48 , wherein the region of brain is the substantia nigra pars compacta. 
     
     
         51 .- 73 . (canceled) 
     
     
         74 . The method of  claim 1 , wherein the XIAP fragment is a 449 amino acid fragment consisting of the XIAP open reading frame lacking 48 C-terminal amino acids and protects dopaminergic neurons. 
     
     
         75 . The method of  claim 40 , wherein the XIAP fragment is a 449 amino acid protein selected from the group consisting of SEQ ID No. 8, SEQ ID No. 13, SEQ ID No. 17, SEQ ID No. 20, SEQ ID No. 22, SEQ ID No. 23, SEQ ID No. 27, SEQ ID No. 30, SEQ ID No. 32, SEQ ID No. 33, SEQ ID No. 36, SEQ ID No. 37, SEQ ID No. 38, SEQ ID No. 41, SEQ ID No. 42, SEQ ID No. 43, SEQ ID No. 46, SEQ ID No. 48, SEQ ID No. 49, SEQ ID No. 51, SEQ ID No. 52, SEQ ID No. 53, SEQ ID No. 55, SEQ ID No. 56, SEQ ID No. 57, SEQ ID No. 58, SEQ ID No. 60, SEQ ID No. 61, SEQ ID No. 62, SEQ ID No. 63, SEQ ID No. 64, and SEQ ID No. 65. 
     
     
         76 . The method of  claim 40 , wherein the XIAP fragment is SEQ ID No. 8 variant consisting of a 449 amino acid protein selected from the group consisting of SEQ ID No. 13, SEQ ID No. 17, SEQ ID No. 20, SEQ ID No. 22, SEQ ID No. 23, SEQ ID No. 27, SEQ ID No. 30, SEQ ID No. 32, SEQ ID No. 33, SEQ ID No. 36, SEQ ID No. 37, SEQ ID No. 38, SEQ ID No. 41, SEQ ID No. 42, SEQ ID No. 43, SEQ ID No. 46, SEQ ID No. 48, SEQ ID No. 49, SEQ ID No. 51, SEQ ID No. 52, SEQ ID No. 53, SEQ ID No. 55, SEQ ID No. 56, SEQ ID No. 57, SEQ ID No. 58, SEQ ID No. 60, SEQ ID No. 61, SEQ ID No. 62, SEQ ID No. 63, SEQ ID No. 64, and SEQ ID No. 65. 
     
     
         77 . The method of  claim 40 , wherein the XIAP fragment is a 449 amino acid fragment consisting of the XIAP open reading frame lacking the 48 C-terminal amino acids and protects dopaminergic neurons. 
     
     
         78 . The method of  claim 40 , wherein the XIAP fragment is a 449 amino acid fragment consisting of the XIAP open reading frame having at least 95% identity to SEQ ID No. 8 and protects dopaminergic neurons. 
     
     
         79 . A method for protecting dopaminergic neurons from apoptosis in a subject comprising:
 identifying a target site in the central nervous system that requires modification; and   delivering a composition comprising a nucleotide sequence encoding X-linked inhibitor of apoptosis protein (XIAP), or a peptide fragment thereof; and a pharmaceutically acceptable carrier, wherein the composition is delivered to the target site in the central nervous system to protect at least one dopaminergic neuron from apoptosis.   
     
     
         80 . The method of  claim 79 , wherein the XIAP fragment is a 449 amino acid protein of SEQ ID No. 8. 
     
     
         81 . The method of  claim 79 , wherein the XIAP fragment is a 449 amino acid fragment consisting of the XIAP open reading frame having at least 95% identity to SEQ ID No. 8 and protects dopaminergic neurons. 
     
     
         82 . The method of  claim 79 , wherein the neurodegenerative disease is associated with protein aggregates. 
     
     
         83 . The method of  claim 79 , wherein the subject has a disorder selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, and Amyloid Lateral Schlerosis (ALS). 
     
     
         84 . The method of  claim 79 , wherein the composition is delivered using stereotaxic delivery. 
     
     
         85 . The method of  claim 79 , wherein the target site in the central nervous system is a region of the brain. 
     
     
         86 . The method of  claim 85 , wherein the region of the brain is selected from the group consisting of basal ganglia, subthalmic nucleus (STN), pedunculopontine nucleus (PPN), substantia nigra (SN), thalamus, hippocampus, cortex, and combinations thereof. 
     
     
         87 . The method of  claim 85 , wherein the region of brain is the substantia nigra pars compacta. 
     
     
         88 . The method of  claim 79 , wherein the XIAP fragment is a 449 amino acid protein selected from the group consisting of SEQ ID No. 8, SEQ ID No. 13, SEQ ID No. 17, SEQ ID No. 20, SEQ ID No. 22, SEQ ID No. 23, SEQ ID No. 27, SEQ ID No. 30, SEQ ID No. 32, SEQ ID No. 33, SEQ ID No. 36, SEQ ID No. 37, SEQ ID No. 38, SEQ ID No. 41, SEQ ID No. 42, SEQ ID No. 43, SEQ ID No. 46, SEQ ID No. 48, SEQ ID No. 49, SEQ ID No. 51, SEQ ID No. 52, SEQ ID No. 53, SEQ ID No. 55, SEQ ID No. 56, SEQ ID No. 57, SEQ ID No. 58, SEQ ID No. 60, SEQ ID No. 61, SEQ ID No. 62, SEQ ID No. 63, SEQ ID No. 64, and SEQ ID No. 65. 
     
     
         89 . The method of  claim 79 , wherein the XIAP fragment is SEQ ID No. 8 variant consisting of a 449 amino acid protein selected from the group consisting of SEQ ID No. 13, SEQ ID No. 17, SEQ ID No. 20, SEQ ID No. 22, SEQ ID No. 23, SEQ ID No. 27, SEQ ID No. 30, SEQ ID No. 32, SEQ ID No. 33, SEQ ID No. 36, SEQ ID No. 37, SEQ ID No. 38, SEQ ID No. 41, SEQ ID No. 42, SEQ ID No. 43, SEQ ID No. 46, SEQ ID No. 48, SEQ ID No. 49, SEQ ID No. 51, SEQ ID No. 52, SEQ ID No. 53, SEQ ID No. 55, SEQ ID No. 56, SEQ ID No. 57, SEQ ID No. 58, SEQ ID No. 60, SEQ ID No. 61, SEQ ID No. 62, SEQ ID No. 63, SEQ ID No. 64, and SEQ ID No. 65.

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