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The term “comparable to” is used herein to mean a value that is as much as 30% less than or more than the reference value to which it is being compared. It is well known that complementarity is the base principle of DNA replication and transcription as it is a property shared between two DNA or RNA sequences, such that when they are aligned antiparallel to each other, the nucleotide bases at each position in the sequences will be complementary, much like looking in the mirror and seeing the reverse of things. In functional assays, EC50 is the concentration of a therapeutic molecule that produces 50% of the biological response, e.g., transcription of mRNA or protein expression. Expression produces a “gene product.” As used herein, a gene product can be either a nucleic acid, e.g., a messenger RNA produced by transcription of a gene, or a polypeptide which is translated from a transcript. The present disclosure provides methods for testing or determining the toxicity (e.g., in vivo acute neurotoxicity) of a molecule by measuring certain characteristics of the molecule.

In one embodiment, the disclosure provides a method of testing, identifying, or determining in vivo acute neurotoxicity of a molecule comprising measuring calcium oscillations in vitro in neuronal cells which are in contact or have been in contact with the molecule. Any other methods disclosed in this application and/or known in the art can further be combined with the calcium oscillation assay and/or the sequence score method. Therefore, identification of the correlations among the calcium oscillation assay, sequence score, and in vivo neurotoxicity allows one to predict the in vivo neurotoxicity based on the calcium oscillation in vitro assay and the sequence score. Not being bound by any theory, the present disclosure identifies (i) a correlation between calcium oscillations of a molecule in vitro in neuronal cells and the sequence score of the molecule (e.g., polynucleotide comprising a sequence), (ii) a correlation between calcium oscillations of a molecule and the in vivo neurotoxicity of the molecule; (iii) a correlation between the sequence score of a molecule (e.g., polynucleotide comprising a sequence) and the in vivo neurotoxicity of the molecule, or (iv) any combination thereof.

In one embodiment, the toxicity, e.g., in vivo acute neurotoxicity, of the molecule is tested by measuring intracellular free calcium oscillations (calcium oscillations) in vitro in neuronal cells which are in contact or have been in contact with the molecule. The present methods can also improve efficiency (i.e., shorten) the evaluation period of candidate molecules by reducing the screening time period for selection of molecules that do not exhibit in vivo acute neurotoxicity. In another embodiment, the toxic side effect is in vivo acute neurotoxicity. In another embodiment, the disclosure includes a method of testing, identifying, or determining in vivo acute neurotoxicity of a molecule comprising (1) adding the molecule to a culture of neuronal cells and (2) measuring calcium oscillations in vitro in the neuronal cells. In some embodiments, the molecule is considered to have an acceptable toxicity (e.g., in vivo acute neurotoxicity) if the molecule does not significantly reduce calcium oscillations in a cell exposed to the molecule compared to the calcium oscillations in a control cell. In another embodiment, the control cell is exposed to a medium that carries the tested molecule to the culture of neuronal cells, e.g., water, buffer, or saline, without the test molecule (i.e., vehicle control).

In some embodiments, the control cell is a cell that has not been exposed to the test molecule, but otherwise is under the same condition as the cells exposed to the test molecule. In another aspect, the disclosure provides a sequence score method to measure or predict toxicity of a molecule. In other embodiments, the disclosure includes a method of selecting or identifying a molecule having tolerable in vivo acute neurotoxicity comprising measuring calcium oscillations in vitro in neuronal cells which are in contact with the molecule, wherein the contacted neuronal cells exhibit calcium oscillations at a level comparable to or higher than that of control cells. In certain embodiments, the disclosure provides a method of testing, identifying, or determining in vivo acute neurotoxicity of a molecule or selecting or identifying a molecule having tolerable in vivo acute neurotoxicity comprising (i) measuring calcium oscillations in vitro in neuronal cells after adding the molecule in a culture of the neuronal cells, wherein the calcium oscillations in the neuronal cells are comparable to or higher than the calcium oscillations of vehicle controls and live girl cams (ii) administering the molecule to a human in need thereof.

In another embodiment, the disclosure provides a method of predicting in vivo acute neurotoxicity of a molecule comprising a step of (1) adding the molecule to a culture of neuronal cells and (2) measuring calcium oscillations in vitro in the neuronal cells. In one embodiment, the toxic side effect includes neurotoxicity in vivo. In another embodiment, the disclosure shows that a molecule exhibiting calcium oscillations in neuronal cells comparable to (i.e., less than 30% or higher than) the calcium oscillations in neuronal cells not exposed to the molecule has a sequence score equal to or greater than 0.2. In other embodiments, the disclosure shows that a molecule having a sequence score equal to or greater than 0.2 exhibits less in vivo neurotoxicity when the molecule is administered to a mammal in vivo. For example, molecules can be assayed to determine if they have low toxicity (e.g., in vivo acute neurotoxicity), and if they are found to have low toxicity, the molecules are selected for use in further testing or administration to a subject such as a mammal. Such methods are helpful to reduce unnecessary killing of animals during testing of the molecule’s toxicity and/or enhance the possibilities that the molecules will be safe for in vivo administration.

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