In the context the term "conjugate" is intended to indicate a heterogeneous molecule formed by the covalent or non-covalent attachment ("conjugation") of the oligomer as described herein to one or more non-nucleotide, or non-polynucleotide moieties. Conjugation (to a conjugate moiety) can enhance the activity, cellular distribution or cellular uptake of the oligomer of the invention. In certain other embodiments, a therapeutic molecule of the invention comprises one or more binding sites derived from a non-immunoglobulin binding molecule. The therapeutic molecules comprising nucleotide sequences can then be subject to the methods of the present invention described elsewhere herein. Adhesion molecules are membrane-bound proteins that allow cells to interact with one another. Conservation of proteins with PEST sequences among different species supports their functional significance. In one embodiment, random therapeutic molecules comprising nucleotide sequences (e.g., oligomers) targeting certain regions of pre-mRNA or mRNA encoding MAPT, BASP1, or APP are prepared to test their toxicities. In other embodiments, the molecules selected according to the present methods are therapeutic molecules.



The molecules selected according to the present methods can be utilized as research reagents for, for example, diagnostics, therapeutics and prophylaxis. In one embodiment, the nucleotide sequence for the present disclosure is DNA. 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 one embodiment, the molecule for the methods disclosed herein is a polypeptide. In one exemplary embodiment, the fibronectin polypeptide is as AdNectin.RTM. Perhaps one of the most well-known modern scandals was Watergate. In some embodiments, the oligomer of the invention comprises at least one LNA unit or at least one 2' substituted modified nucleoside. US Publication No. 2011/0130441, which was published Jun. 2, 2011, refers to oligomeric compounds having at least one bicyclic nucleoside attached to the 3' or 5' termini by a neutral internucleoside linkage. In a further embodiment the oligonucleotide comprises at least one modified internucleoside linkage. In other embodiments, a therapeutic molecule of the invention comprises a binding site from a repeat protein. This protein also undergoes N-terminal myristoylation. In certain embodiments, the therapeutic molecules (e.g., oligomers) target a pre-mRNA encoding an amyloid precursor protein.



Other examples of therapeutic molecules not derived from antibody molecules include receptor binding sites and ligand binding sites which are discussed in more detail infra. 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. Thrombopoeitin (TPO; stem-cell factor (SCF), thrombopoietin (TPO, c-Mpl ligand), and the Wnt polypeptides (U.S. Polypeptides useful for the disclosure can comprise a variable region or portion thereof (e.g. a VL and/or VH domain) derived from an antibody using art recognized protocols or may be obtained from an art-recognized antibody using standard molecular biology techniques. 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.. Cytokines have pleiotropic effects on the proliferation, differentiation, and functional activation of lymphocytes. As used herein the term "inflammatory disease or disorder" includes diseases or disorders which are caused, Https://Mycamscom.Com/ at least in part, or exacerbated by inflammation, e.g., increased blood flow, edema, activation of immune cells (e.g., proliferation, cytokine production, or enhanced phagocytosis). The invention also provides for a conjugate comprising the oligomer according to the invention as herein described, and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said oligomer.



Examples of non-nucleotide or non-polynucleotide moieties include macromolecular agents such as proteins, fatty acid chains, sugar residues, my cams glycoproteins, polymers, or combinations thereof. Pat. No. 8,906,356: for example, amino acid residue 91, 126, or both, e.g., V91R, Q126T, or both. Such molecules are described in the art (see e.g., U.S. In other embodiments, a therapeutic molecule of the invention comprises a binding site from a single chain binding molecule (e.g., a single chain variable region or scFv). In another embodiment, a therapeutic molecule of the invention comprises a binding site from an Anticalin.RTM. Small molecules can comprise any therapeutic molecules that is not a peptide, My cams a polypeptide, a protein, and a polynucleotide. Such binding molecules comprise a binding site portion which retains the conformation of an immunoglobulin fold and is capable of specifically binding an IGF1-R epitope. Antigen binding portions can be produced by recombinant or biochemical methods that are well known in the art.