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Sirna-mediated gene silencing of synucleinRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Genetically Modified Micro-organism, Cell, Or Virus (e.g., Transformed, Fused, Hybrid, Etc.)Sirna-mediated gene silencing of synuclein description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070172462, Sirna-mediated gene silencing of synuclein. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation-in-part of International Application No. PCT/US2005/034516, filed Sep. 27, 2005, which claims the benefit of U.S. Provisional Application Ser. No. 60/614,112, filed Sep. 29, 2004, these references are incorporated herein in their entirety. FIELD OF THE INVENTION [0003] The present invention generally relates to methods and systems for siRNA gene silencing and more specifically relates to methods and systems for siRNA gene silencing of the .alpha.-synuclein gene and synuclein gene family members. BACKGROUND [0004] RNA interference (RNAi) refers to the process of sequence-specific post transcriptional gene silencing mediated by small interfering RNAs (siRNA) (Fire et al., 1998, Nature, 391, 806-11). Long double stranded RNA (dsRNA) in cells stimulates the activity of a ribonuclease III enzyme referred to as dicer. Dicer is involved in the processing of the long dsRNA into short pieces of siRNA (Bernstein et al., 2001, Nature, 409, 363-6). siRNAs derived from dicer activity are typically about 21-23 nucleotides in length and include duplexes of about 19 base pairs. [0005] The RNAi response also features an endonuclease complex containing a siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single stranded RNA having sequence complementary to the antisense strand of the siRNA duplex. Cleavage of the target RNA takes place in the middle of the region complementary to the antisense strand of the siRNA duplex (Elbashir et al., 2001, Nature, 411, 494-498). [0006] siRNA mediated RNAi has been studied in a variety of systems. Recent work in Drosophila embryonic lysates has revealed certain requirements for siRNA length, structure, chemical composition, and sequence that are essential to mediate efficient RNAi activity (Elbashir et al., 2001, EMBO J., 20, 6877-88). RNAi technology has been used in mammalian cell culture, where a siRNA-mediated reduction in gene expression has been accomplished by transfecting cells with synthetic RNA oligonucleotides (Caplen et al., 2001, Proc. Natl. Acad. Sci., U.S.A., 98, 9742-7; Elbashir et al., 2001, Nature, 411, 494-8). The ability to use siRNA-mediated gene silencing in mammalian cells combined with the high degree of sequence specificity allows RNAi technology to be used to selectively silence expression of mutant alleles or toxic gene products in dominantly inherited diseases, including neurodegenerative diseases. Several neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Spinocerebellar Ataxia Type 1, Type 2, and Type 3, and dentatorubral pallidoluysian atrophy (DRLPA), have proteins identified that are involved in the overall pathogenic progression of the disease. [0007] siRNA-mediated gene silencing of mutant forms of human ataxin-3, Tau and TorsinA, genes which cause neurodegenerative diseases such as spinocerebellar ataxia type 3, frontotemporal dementia and DYTI dystonia respectively, has been demonstrated in cultured cells (Miller et al. 2003, Proc. Natl. Acad. Sci., U.S.A., 100, 7195-7200; Gouzales-Alegre et al., 2003, Ann. Neurol. 53, 781-7). [0008] .alpha.-synuclein (.alpha.-syn) is involved in the pathogenesis of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), the Lewy body variant of Alzheimer's disease (LBVAD), multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1), as well as sleep and other disorders. Common to all of these diseases, termed synucleinopathies, are proteinaceous insoluble inclusions in the neurons and the glia which are composed primarily of .alpha.-syn. [0009] .alpha.-syn is part of a large family of proteins including .beta.- and .gamma.-synuclein and synoretin. .alpha.-syn is expressed in the normal state associated with synapses and plays a role in neural plasticity, learning and memory. Mutations in the human .alpha.-syn (h-.alpha.-syn) gene that enhance the aggregation of .alpha.-syn have been identified (alanine to threonine substitution at position 53 (A53T) and alanine to proline at position 30 (A30) and are associated with rare forms of autosomal dominant forms of PD. Altered h-.alpha.-syn function triggers neurodegenerative processes associated with PD such as the selective loss of dopaminergic neurons in the substantia nigra pars compacta leading to substantial depletion of dopamine in the striatum resulting in severe motor impairment (Dawson et al., 2002, Nat. Neurosci., November; 5 Suppl: 1058-61). Abnormal accumulation of wild-type or mutant .alpha.-syn impairs proteasome function, interferes with vesicular dopamine storage, renders endogenous dopamine toxic, and contributes to mitochondrial dysfunction (Polymeropoulos, M., 2000, Ann. NY. Acad. Sci., 920, 28-32, Lotharius et al., 2002, Nature Reviews Neurosci. 3, 932-42). [0010] A need exists for a siRNA-mediated gene silencing methods and systems for silencing .alpha.-syn and its family members. BRIEF SUMMARY [0011] In one aspect of the present invention, a small interfering RNA (siRNA) that down regulates expression of a synuclein gene is provided. [0012] In another aspect of the present invention, a composition is provided that includes a siRNA in an amount sufficient to down regulate expression of a synuclein gene, wherein the siRNA comprises a nucleotide sequence substantially complementary to 15-30 consecutive nucleotides of SEQ ID NO: 1. [0013] In yet another aspect of the present invention, a vector is provided that includes a promoter and a nucleotide sequence operatively linked to the promoter which comprises 15-30 consecutive nucleotides of SEQ ID NO: 1 wherein the nucleotide sequence encodes a siRNA that down regulates a synuclein gene. [0014] In another aspect of the present invention, a method of reducing expression of a synuclein gene in a cell is provided. The method includes introducing into a cell a siRNA in an amount effective to down regulate expression of the synuclein gene. The siRNA includes a nucleotide sequence substantially complementary to 15-30 consecutive nucleotides of SEQ ID NO: 1. [0015] In yet another aspect of the present invention, a method of reducing cell death is provided. The method includes introducing into a cell a siRNA in an amount effective to down regulate expression of the synuclein gene. The siRNA includes a nucleotide sequence substantially complementary to 15-30 consecutive nucleotides of SEQ ID NO: 1. [0016] In another aspect of the present invention, a method of treating a neurodegenerative disease or a synucleinopathy in a subject is provided. The method includes administering to the subject a therapeutically effective amount of a siRNA comprising a nucleotide sequence substantially complementary to 15-30 consecutive nucleotides of SEQ ID NO: 1 wherein the expression of the synuclein gene is down regulated. [0017] Advantages of the present invention will become more apparent to those skilled in the art from the following description of the preferred embodiments of the present invention that have been shown and described by way of illustration. As will be realized, the invention is capable of other and different embodiments, and its details are capable of modification in various respects. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive. DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS [0018] The present invention utilizes siRNA-mediated gene silencing for silencing the synuclein family of genes. [0019] The practice of the present invention will employ, unless otherwise indicated, conventional methods of virology, microbiology, molecular biology and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Sambrook, et al. Molecular Cloning: A Laboratory Manual (Current Edition); DNA Cloning: A Practical Approach, vol. I & II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., Current Edition); Nucleic Acid Hybridization (B. Hames & S. Higgins, eds., Current Edition); Transcription and Translation (B. Hames & S. Higgins, eds., Current Edition); CRC Handbook of Parvoviruses, vol. I & II (P. Tijssen, ed.); Fundamental Virology, 2nd Edition, vol. I & II (B. N. Fields and D. M. Knipe, eds.) [0020] Definitions [0021] The term "nucleic acid" refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form, composed of monomers (nucleotides) containing a sugar, phosphate and a base that is either a purine or pyrimidine. Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides, conservatively modified variants thereof, complementary sequences, and degenerate codon substitutions that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Continue reading about Sirna-mediated gene silencing of synuclein... 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