For NOR, data are analyzed using either a paired t-test for within-group analyses or by an ANOVA followed by a Dunnett's post-hoc test for between group analyses. For Morris Water Maze (MWM), a repeated MWM ANOVA is used to analyze the acquisition phase and a one-way ANOVA followed by Dunnett's post-hoc for probe trial analyses. In one embodiment, a behavioral score is obtained with a water maze test, such as the Morris Water Maze. In another embodiment, a molecule of the invention targets one or more endogenously produced proteins or peptides in vivo, one or more mRNAs or pre-mRNAs encoding the proteins or peptides, or one or chatturbatt more genes encoding the proteins or peptides. In other embodiments, the present invention is also directed to a method of selecting or identifying a molecule having tolerable in vivo neurotoxicity by performing in vivo tolerability studies. The molecules to be screened or selected according to the present invention include therapeutic molecules. In certain embodiments, a therapeutic molecule is a protein comprising cytokines, enzymes, growth factors, monoclonal antibody, antibody fragments, single-chain antibodies, albumin, immunoglobulins, clotting factors, chatturbatt somatropin, amylase, lipase, protease, cellulose, urokinase, galactosidase, staphylokinase, hyaluronidase, tissue plasminogen activator, or any combination thereof. In still other embodiments, the method comprising a calcium oscillation assay, a sequence score method, and/or in vivo tolerability test can further comprise administering the selected molecule to a subject in need thereof.
The in vivo tolerability study can also be used after selecting a small number of candidate molecules after performing the calcium oscillation assay and/or sequence score calculation. In some embodiments, fluorescence of the stained cells (including stained individual cells) can be measured by confocal, or standard, fluorescence microscopy, optionally at a number of time points or continuously (e.g., real-time) to provide, for example, time lapse measurements. In one embodiment, the calcium oscillations measured in the present methods are the cumulative increase in calcium oscillations within a culture of neuronal cells, whereby the time to reach the maximum fluorescence signal constitutes the magnitude of the calcium response. In certain embodiments, the change in tubulin intensity is measured along with one or both of the change in calcium oscillation, sequence score, and/or in vivo tolerability assay. In one embodiment, the method comprises a behavioral test score, which can be measured by administering the molecule to a mammal and grading the mammal's behavioral performance. In some embodiments, the molecule comprises a polynucleotide (e.g., oligomer), a nucleotide, or a small molecule.The disclosure also provides a method of administering a molecule to a subject for the treatment of a neurological disease or condition. The present disclosure is also directed to a method of testing or determining in vivo neurotoxicity of a molecule (e.g., polynucleotide) comprising a nucleotide sequence. The NOR testing can be used similar to the test shown in Example 5, or can be modified as necessary. Example 5 herein. In another embodiment, a spatial learning and memory test can be assessed by a modified Morris Water Maze test as necessary. In certain embodiments, the behavioral test is a short term memory test, a spatial learning and memory test, a gait analysis test, or any combination thereof. Spatial learning and memory can be assessed based on a Morris Water Maze test as shown in Morris J. Neurosci. Short term recognition memory can be measured using the novel object recognition (NOR) task. In certain embodiments, the methods of the disclosure further comprise measuring long term in vivo toxicities of a molecule. Therefore, for therapeutics, an animal or a human, suspected of having a disease or disorder can be treated by administering molecules in accordance with this disclosure. In certain embodiments, the present disclosure provides a method of identifying or determining a molecule having intolerable in vivo neurotoxicity comprising measuring calcium oscillations in vitro in neuronal cells after being in contact with the molecule in the neuronal cells.
In certain embodiments, molecules comprising nucleotide sequences that have a sequence score below the set thresholds are considered to be molecules that have unacceptable neurotoxicity. In these embodiments, molecules having a sequence score below the set thresholds are considered as having a risk of toxic side effects if administered to a subject. Having matched high libidos is a lot of fun, especially if you can maintain intimacy and closeness at the same time. In an embodiment, the oscillation frequency can be determined by a time interval from commencement of a first oscillation in intracellular calcium flux to a commencement of a second oscillation in intracellular calcium flux. The term «oscillation frequency» refers to the time between oscillations. For example, long term toxicities can be determined by measuring the change in tubulin intensity in a cell by the molecule when the cell comes in contact with a molecule. The molecules selected according to the present methods can be utilized as research reagents for, for example, diagnostics, therapeutics and prophylaxis. For example, a nucleotide sequence of ATGCATGCATGCATGC (SEQ ID NO: 3) has a sequence score of 0 ((4Cs-4Gs)/16).]]>
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