The invention further provides for a molecule according to the invention, for use for the treatment of one or more of the diseases associated with neuronal cells or referred to herein, such as a disease selected from Alzheimer’s disease, progressive supranuclear palsy, Down syndrome, dementia pugilistica (chronic traumatic encephalopathy and other traumatic brain injury), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Lytico-Bodig disease (Parkinson-dementia complex of Guam), Tangle-predominant dementia, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, Hemimegalencephaly, tuberous sclerosis, Hallervorden-Spatz disease, Pick’s disease, corticobasal ganglionic degeneration, argyrophilic grain disease, corticobasal degeneration, lipofuscinosis, frontotemporal dementia, supranuclear palsy, and frontotemporal lobar degeneration (reviewed in Frost et. In certain embodiments, the disease or condition is progressive supranuclear palsy, Down syndrome, dementia pugilistica (chronic traumatic encephalopathy and other traumatic brain injury), frontotempotal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Lytico-Bodig disease (Parkinson-dementia complex of Guam), Tangle-predominant dementia, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, Hemimegalencephaly, tuberous sclerosis, Hallervorden-Spatz disease, Pick’s disease, corticobasal ganglionic degeneration, argyrophilic grain disease, corticobasal degeneration, Cams online sex lipofuscinosis, frontotemporal dementia, supranuclear palsy, and frontotemporal lobar degeneration, a disease of brain network dysfunction (e.g., all forms of epilepsy and depression), dravet syndrome, a spinal cord disorder, a peripheral neuropathy, a cranial nerve disorder (e.g., Trigeminal neuralgia), an autonomic nervous system disorder (e.g., dysautonomia or multiple system atrophy), a movement disorder of a central and peripheral nervous system (e.g., Parkinson’s disease, essential tremor, cams online sex amyotrophic lateral sclerosis, Tourette’s Syndrome, multiple sclerosis or various types of peripheral neuropathy), a sleep disorder (e.g., Narcolepsy), migraine or other types of headache (e.g., cluster headache and tension headache), lower back and neck pain, central neuropathy, a neuropsychiatric illness, attention deficit hyperactivity disorder, autism, Huntington’s disease, Rett Syndrome, Angelman syndrome, organic psychosis, an infection of the brain or spinal cord (including meningitis), or a prion disease), anemia, cancer, leukemia, an inflammatory condition or an autoimmune disease (e.g. arthritis, psoriasis, lupus erythematosus, multiple sclerosis), a bacterial infection, and any combination thereof.
In certain other embodiments, the disease or condition is a neurodegenerative disease with tauopathy, e.g., progressive supranuclear palsy, frontotemporal dementia-tau (FTD-tau), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), corticobasal degeneration (CBD), traumatic brain injury, chronic traumatic encephalopathy, HIV associated neurocognitive disorders, Argyrophilic grain disease, Down syndrome-Alzheimer’s disease, Amnestic mild cognitive impairment-Alzheimer’s disease, Parkinson’s disease dementia, Hallervorden-Spatz disease (Pantothenate kinase-associated neurodegeneration), Niemann Pick disease type C, Myotonic dystrophy, Amyotrophic lateral sclerosis, Parkinson’s disease or Huntington’s disease. In certain other embodiments, the disease or condition for treatment or prophylaxis is a neurodegenerative disease with tauopathy. The molecules selected according to the present methods can be utilized as research reagents for, for example, diagnostics, therapeutics and prophylaxis. 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. In some embodiments, the molecule exhibits tubulin intensity in a cell greater than or equal to 99%, greater than or equal to 98%, greater than or equal to 97%, greater than or equal to 96%, greater than or equal to 95%, greater than or equal to 90%, greater than or equal to 85%, greater than or equal to 80%, greater than or equal to 75%, or greater than or equal to 70% of tubulin intensity in a cell that is not exposed to the molecule, i.e., a control cell, as defined above.
In some embodiments, the tubulin intensity in a cell that is not exposed to the tested molecule is referred to as the tubulin intensity in a control cell. Examples of assays measuring the change in tubulin intensity in a cell are provided below. In some embodiments, the molecule reduces less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% of the tubulin intensity in a vehicle control cell. 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. Not being bound by any theory, the molecule with less reduction (70% or higher) in calcium oscillations compared to a control (e.g., saline) has a higher sequence score (e.g., higher than 0.2). Also not being bound by any theory, the molecule with less reduction (70% or higher) in calcium oscillations compared to a control and a higher sequence score (higher than 0.2) has a lower in vivo behavioral score (e.g., less than 4). In other embodiments, the molecule with less reduction (70% or higher) in calcium oscillations compared to a control and a higher sequence score (higher than 0.2) has tolerable in vivo acute neurotoxicity.
In some embodiments, the disclosure provides a method of treating a mammal, e.g., a human, comprising (1) selecting a molecule having tolerable in vivo acute neurotoxicity as described elsewhere herein (e.g., calcium oscillation assay, sequence score calculation, and/or in vivo tolerability study) and (2) administering the molecule to the mammal. 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 disclosure also provides a method of administering a molecule to a subject for the treatment of a neurological disease or condition. 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. Further provided are methods of treating a mammal, such as treating a human, suspected of having or being prone to a disease or condition by administering a therapeutically or prophylactically effective amount of one or more of the molecules of the disclosure.
In one embodiment, the behavioral performance is measured by injecting the molecule to a mammal, e.g., a brain of a mammal, e.g., intracerebroventricular (ICV) or intrathecal (IT) administration, and grading the mammal’s behavioral performance on a scale of 0 to 4. In certain embodiments, the behavioral score is less than or equal to the total score of 3, the total score of 2, the total score of 1, or the total score of 0. In some embodiments, the behavioral score is determined as described in Example 5 below. Therapeutic molecules are injected into a laboratory animal by ICV or IT. The laboratory animal can be a mammal, e.g., a rodent, such as a mouse, rat, guinea pig or hamster, but can also be another animal typically used in laboratory testing. The present methods can further comprise measuring a behavioral performance of an animal by a molecule. In certain embodiments, the animals are observed at about 0.5 hour, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours or about 5 hours following the injection of the molecule. In certain embodiments, the invention provides a method for both selecting a molecule and then utilizing the molecule.
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