The term "oligomer" in the context of the present invention, refers to a molecule formed by covalent linkage of two or more nucleotides (i.e., an oligonucleotide). Sequence score for each oligomer was calculated by inserting appropriate numbers in the formula: ((number of C nucleotides or the analogs-number of G nucleotides)/nucleotide length (number) in the oligomer). The oligomer comprises a contiguous nucleotide sequence of from about 10 to about 50, such as 10-20, 16-20, 10-30, 10-35, 10-40, or 10-45 nucleotides in length. FIG. 3: Correlation analysis of sequence score vs. FIG. 6: shows Tau protein reduction by exemplary antisense oligonucleotides. FIG. 5: shows in vivo tolerability of exemplary antisense oligonucleotides. FIG. 5 lists the ASO identification number, ASO sequence, SEQ ID Number, target start and end positions on the MAPT pre-mRNA sequence, in vivo acute tolerability score (as discussed in Example 6 below) and the percent of brain MAPT mRNA remaining after administration (as also discussed in Example 6 below). FIG. 6 lists the SEQ ID number, oligomer name, ASO identification number, ASO sequence, target start and end positions on the MAPT pre-mRNA sequence, target start on the mature mRNA sequence and normalized Tau/Tuj-1 and Tuj-1 immunocytochemistry values (as discussed in Example 7 below).



FIG. 4 lists the oligomer name, ASO identification number, ASO sequence, SEQ ID Number, target start and end positions on the MAPT pre-mRNA sequence, and calcium oscillation data as a percent of control (as discussed in Example 2 below). Examples of oligomers with mismatched bases are provided in FIG. 7 as "mm." The specific mismatched base-pairs are bolded, underlined, italicized, and highlighted. Examples of oligomers with mismatched bases are provided in FIG. 4 as "mm." The specific mismatched base-pairs are bolded, underlined, italicized, and highlighted. FIG. 2: Graph showing inhibition of AMPA mediated calcium oscillations by antisense oligomers as an indication of neuronal network activity disruption. FIG. 1: Graph demonstrating primary neuronal spontaneous calcium oscillations. FIG. 4: shows the impact of Tau antisense oligonucleotide on spontaneous calcium oscillations in primary neurons. E74. The method of any one of Embodiments 63 to 73, wherein the molecule is an antisense oligonucleotide. E79. An antisense oligonucleotide for use in treating a neurological disease or condition in a subject in need thereof, wherein calcium oscillations in neuronal cells that are in contact with the antisense oligonucleotide are about 70% or higher, about 75% or higher, about 80% or higher, about 85% or higher, about 90% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 100% or higher, about 120% or higher, about 140% or higher, about 160% or higher, about 180% or higher, about 200% or higher, about 220% or higher, about 240% or higher, or about 250% or higher compared to the calcium oscillations in vehicle control cells.



In one embodiment, the therapeutic molecule is capable of initiating transduction of a signal which results in death of the cell (e.g., by a cell signal induced pathway, by complement fixation or exposure to a payload (e.g., a toxic payload) present on the binding molecule), or which modulates a disease or disorder in a subject (e.g., by mediating or promoting cell killing, or by modulating the amount of a substance which is bioavailable (e.g., by enhancing or reducing the amount of a ligand such as TNF.alpha. E78. The molecule of Embodiment 77, wherein the disease or condition is associated with a neuronal cell. Proteins that are therapeutic molecules include, but are not limited to, antibodies or antigen-binding fragments thereof, fusion proteins, cytokines, cell surface receptors, hormones, growth factors, or any combination thereof. You are only allowed to send only a limited number of emails per day. The terms "antisense oligomer," "antisense oligonucleotide," and "ASO" as used herein are interchangeable with the term "oligomer." In various embodiments, the oligomer of the invention does not comprise RNA (units). The ASO and other oligomerss that behaved similarly, were shown to negatively impact central nervous system (CNS) network activity in vivo and electrophysiologic spontaneous neuronal activity in vitro (data not shown).



E86. In the methods of Embodiments 81 to 85, Free Private Sexcam the improvement further comprising measuring reduction of in vitro expression of a target protein of the molecule. E82. In a method of selecting or identifying a molecule having tolerable in vivo neurotoxicity, the improvement comprising measuring calcium oscillations in vitro in neuronal cells which are in contact with the molecule, wherein the neuronal cells in contact with the molecule exhibit calcium oscillations at a level comparable to or higher than that of vehicle control cells. Stay in control and start where you want to start. Antisense oligomer inhibition of spontaneous calcium oscillations mediated by either NMDA or AMPA was assessed in the presence or absence of 1 mM MgCl.sub.2 (representing 100% control in each case). Addition of 25 .mu.M antisense oligomers (TGTgatgcaggaGTT) (SEQ ID NO: 304) (ASO-00007) inhibited AMPA receptor but not NMDA receptor mediated oscillations. Calcium oscillations were reduced further, by about 80%, when N-methyl-D-aspartate (NMDA) receptor function was blocked by 1 mM MgCl.sub.2 (NMDA labeled bar shown). E66. The method of any one of Embodiments 63 to 65, wherein the calcium oscillations are AMPA receptor dependent. Primary neuronal spontaneous calcium oscillations were measured as described previously (Murphy et.



E75. The method of any one of Embodiments 63 to 74, wherein when the molecule is administered to laboratory animals, more than 50% of the animals survive. E69. The method of any one of Embodiments 63 to 68, wherein the molecule comprises a small molecule, a polynucleotide, a protein, a peptide, or any combination thereof. Non-limiting examples of the therapeutic molecules include oligomers, one or more nucleotides, one or more nucleosides, one or more amino acids, polynucleotides, peptides, proteins, polypeptides, or small molecule compounds that are naturally occurring, modified, recombinantly produced, or chemically synthesized. It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "a molecule," is understood to represent one or more molecules. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. With all of the setup, software and hardware managed for you, you'll be able to spend your time marketing your business without having to worry about the technical details. We won't ever get involved with ones that have illegal content or engage in shady business practices.