In certain embodiments, the oligomers target a pre-mRNA or mRNA encoding brain acid soluble protein 1 (BASP1). Examples of genes that can be targeted by nucleotide sequences selected by the methods of the present invention include, but are not limited to, microtubule-associated protein tau (encoded by the MAPT gene), brain acid soluble protein 1 (encoded by the BASP1 gene), or amyloid precursor protein (encoded by the APP gene). PEST sequences typically occur in proteins with high turnover rates. The BASP1 gene encodes a membrane bound protein with several transient phosphorylation sites and PEST motifs. Conservation of proteins with PEST sequences among different species supports their functional significance. Nucleotide sequences of any type can be analyzed using the methods of the current invention. In certain embodiments, nucleotide sequences targeting pre-mRNA or mRNAs that are primarily expressed in neuronal cells as proteins are analyzed for selected characteristics as discussed elsewhere herein. In other embodiments, the nucleotide sequence comprises at least 15 nucleotides, at least 20 nucleotides, at least 25 nucleotides, at least 30 nucleotides, at least 35 nucleotides, at least 40 nucleotides, at least 45 nucleotides, at least 50 nucleotides, at least 55 nucleotides, at least 60 nucleotides, at least 65 nucleotides, at least 70 nucleotides, at least 80 nucleotides, at least 90 nucleotides, at least 100 nucleotides, at least 150 nucleotides, at least 200 nucleotides, at least 300 nucleotides, at least 400 nucleotides, at least 500 nucleotides, at least 600 nucleotides, at least 700 nucleotides, at least 800 nucleotides, at least 900 nucleotides, at least 1000 nucleotides, at least 2000 nucleotides, at least 3000 nucleotides, or cams online sex at least 4000 nucleotides.





In yet other embodiments, the nucleotide sequence comprises at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides, at least six nucleotides, at least seven nucleotides, at least eight nucleotides, at least nine nucleotides, at least 10 nucleotides, or at least 11 nucleotides in length. In one embodiment, a polypeptide of the invention combines the binding site(s) of the ligand or receptor (e.g. the extracellular domain (ECD) of a receptor) with at least one genetically-fused Fc region (i.e., scFc region). Growth factors or their receptors (or receptor binding or ligand binding portions thereof) may be incorporated in the fusion proteins of the invention. Exemplary growth factor receptors which may be used as therapeutic moieties of the invention include EGF receptors; VEGF receptors (e.g. Flt1 or Flk1/KDR), PDGF receptors (WO 90/14425); HGF receptors (U.S. Exemplary cytokines that can be inhibited using such heterodimeric receptors include: ILL IL-2, IL-3, IL-4, IL-5, IL-3, IL-4, IL-5, IL-11, IL-15, GMCSF, LIF, INF.alpha., and TGF.beta.. In one embodiment, antagonists to cytokines that utilize an .beta. In another embodiment, the nucleotide sequence for the present disclosure is RNA.



In some embodiments, the nucleotide sequence encodes any polypeptide disclosed above in Sections III.A, III.B, and III.C.1-III.C.5. In this regard, the nucleotide sequence of the invention can affect indirect inhibition of the protein click through the following website a reduction in mRNA levels, typically in a mammalian cell, such as a human cell, such as a neuronal cell. In still other embodiments, the nucleotide sequence for the disclosure comprises one or more chemically modified nucleotides. I had male acquaintances I had casually dated that were simply just friends still in my life. Nood is still growing, but the site already features a clean user interface with quick load times and zero skeevy ads. In one exemplary embodiment, the binding site of the receptor-binding portion of a ligand is derived from a ligand belonging to the TNF ligand superfamily described supra (e.g., CD40L). In certain embodiments, the ligand binding portion of a receptor is derived from a receptor selected from a receptor of the Immunoglobulin (Ig) superfamily (e.g., a soluble T-cell receptor, e.g., mTCR.RTM. In other embodiments, the binding site or domain of the receptor-binding portion of a ligand is derived from a ligand bound by an antibody or antibody variant described supra. For example, the ligand can bind a receptor selected from the group consisting of a receptor of the Immunoglobulin (Ig) superfamily, a receptor of the TNF receptor superfamily, a receptor of the G-protein coupled receptor (GPCR) superfamily, a receptor of the Tyrosine Kinase (TK) receptor superfamily, a receptor of the Ligand-Gated (LG) superfamily, a receptor of the chemokine receptor superfamily, IL-1/Toll-like Receptor (TLR) superfamily, and a cytokine receptor superfamily.



Pat. Nos. 6,403,764 and 6,506,874); Erythropoietin (EPO); Thrombopoeitin (TPO; stem-cell factor (SCF), thrombopoietin (TPO, c-Mpl ligand), and the Wnt polypeptides (U.S. Exemplary growth factors include Vascular Endothelial Growth Factor (VEGF) and its isoforms (U.S. Pat. No. 5,194,596); Fibroblastic Growth Factors (FGF), including aFGF and bFGF; atrial natriuretic factor (ANF); hepatic growth factors (HGFs; U.S. Such molecules are described in the art (see e.g., U.S. TGF-alpha and TGF-beta (WO 90/14359), osteoinductive factors including bone morphogenetic protein (BMP); insulin-like growth factors-I and -II (IGF-I and IGF-II; U.S. In certain embodiments, the therapeutic molecules (e.g., oligomers) target a pre-mRNA encoding an amyloid precursor protein. APP is best known as the precursor molecule whose proteolysis generates beta amyloid (A.beta.), a 37 to 49 amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 365 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease. For example, natural variants of Tau protein can contain one or more amino acid substitutions selected from: RSH, RSL, D285N, V289A, K574T, L583V, G589V, N596K, N613H, P618L, P618S, G620V, S622N, K634M, S637F, V654M, E659V, K6861, G706R, R723W, or any combinations thereof.



Therefore, the oligomers of the present invention can be designed to reduce or inhibit expression of the natural variants of the Tau protein. Natural variants of the MAPT gene product are known. In certain embodiments, the oligomers target microtubule-associated protein tau (MAPT). In a pathologic state associated with disease, MAPT is also known as neurofibrillary tangle protein or paired helical filament-tau (PHF-tau). This protein also undergoes N-terminal myristoylation. 007398. The sequence for Tau protein can be found under publicly available Accession Numbers: P10636, P18518, Q14799, Q15549, Q15550, Q15551, Q1RMF6, Q53YB1, Q5CZI7, QSXWFO, Q6QT54, Q9UDJ3, Q9UMH0, Q9UQ96, each of which is incorporated by reference herein in its entirety. In certain embodiments, the nucleotide sequence binds or hybridizes to a nucleic acid sequence (DNA or RNA, e.g., pre-mRNA or mRNA) encoding one or more polypeptides disclosed above in Sections III.A., III.B., and III.C.1-III.C.5. In one embodiment, the nucleotide sequence for the present disclosure is DNA. The term "nucleotide sequence" herein means the molecule in which more than two nucleotides are connected to each other as a sequence.