This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with CNS disorders. It also relates to the use of an α5-containing GABA.sub.A receptor agonist (e.g, an α5-containing GABA.sub.A receptor positive allosteric modulator) in treating cognitive impairment associated with CNS disorders in a subject in need or at risk thereof, including age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI, Age-Associated Memory Impairment, Age Related Cognitive Decline, dementia, Alzheimer's Disease (AD), prodromal AD, PTSD, schizophrenia, bipolar disorder, ALS, cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. It also relates to the use of an α5-containing GABA.sub.A receptor agonist (e.g., an α5-containing GABA.sub.A receptor positive allosteric modulator) in treating brain cancers (including brain tumors, e.g., medulloblastomas), and cognitive impairment associated therewith.

This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with CNS disorders. It also relates to the use of an α5-containing GABA.sub.A receptor agonist (e.g, an α5-containing GABA.sub.A receptor positive allosteric modulator) in treating cognitive impairment associated with CNS disorders in a subject in need or at risk thereof, including age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI, Age-Associated Memory Impairment, Age Related Cognitive Decline, dementia, Alzheimer's Disease (AD), prodromal AD, PTSD, schizophrenia, bipolar disorder, ALS, cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease, autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. It also relates to the use of an α5-containing GABA.sub.A receptor agonist (e.g., an α5-containing GABA.sub.A receptor positive allosteric modulator) in treating brain cancers (including brain tumors, e.g., medulloblastomas), and cognitive impairment associated therewith.

The present invention features a method of reducing tactile dysfunction or anxiety in a subject diagnosed with Autism Spectrum Disorder, Rett Syndrome, or Fragile X syndrome by administering a GABA.sub.A agent having reduced blood brain barrier or by expressing a nucleic acid encoding an exogenous alpha or beta subunit of a GABA.sub.A receptor in dorsal root ganglion neurons in the subject using a vector.

This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with an integrin inhibitor. In particular, the disclosure features the topical treatment of sections and subsections of the gastrointestinal tract by integrin inhibitors (like vedolizumab) using an ingestible device that can detect its whereabouts in the Gl tract by using reflectance and which is programmed to release the drugs at a given site or proximal thereto, to treat gastrointestinal inflammatory diseases. The device has hardware storage devices with instructions on board to determine the location and release the formulations. Combination therapies are claimed as well in which the integrin inhibitor is added systemically and another agent (e.g. JAK inhibitor, TNF-alpha inhibitor or IL-12/IL-23 inhibitor) is added topically by means of the ingestible device. The topical administration is said to reduce the side effects associated with systemic treatment.

This disclosure features methods and compositions for treating diseases of the gastrointestinal tract with an integrin inhibitor. In particular, the disclosure features the topical treatment of sections and subsections of the gastrointestinal tract by integrin inhibitors (like vedolizumab) using an ingestible device that can detect its whereabouts in the Gl tract by using reflectance and which is programmed to release the drugs at a given site or proximal thereto, to treat gastrointestinal inflammatory diseases. The device has hardware storage devices with instructions on board to determine the location and release the formulations. Combination therapies are claimed as well in which the integrin inhibitor is added systemically and another agent (e.g. JAK inhibitor, TNF-alpha inhibitor or IL-12/IL-23 inhibitor) is added topically by means of the ingestible device. The topical administration is said to reduce the side effects associated with systemic treatment.

The present invention relates generally to methods of treatment of Alzheimer's Disease or Mild Cognitive Impairment which are adapted to avoid negative interactions between combinations of therapeutics. In particular there are disclosed such methods of treatment in which the order of therapeutics is actively controlled to mitigate homeostatic downregulation prior to administration of active, for example disease modifying, therapeutic agents. In certain embodiments therapy with symptomatic treatments (such as modifiers of the activity of acetylcholine or glutamate neurotransmitters) may subsequently be combined with the disease modifying or other active treatment. The invention also applies the findings in relation to homeostatic downregulation to novel methods of clinical trial design.

The present invention relates generally to methods of treatment of Alzheimer's Disease or Mild Cognitive Impairment which are adapted to avoid negative interactions between combinations of therapeutics. In particular there are disclosed such methods of treatment in which the order of therapeutics is actively controlled to mitigate homeostatic downregulation prior to administration of active, for example disease modifying, therapeutic agents. In certain embodiments therapy with symptomatic treatments (such as modifiers of the activity of acetylcholine or glutamate neurotransmitters) may subsequently be combined with the disease modifying or other active treatment. The invention also applies the findings in relation to homeostatic downregulation to novel methods of clinical trial design.

The invention provides a device comprising: at least one biocompatible polymer, and an eutectic composition comprising a first agent and an agent capable of forming a eutectic composition with the first agent; or one or more fatty acids; or one or more fatty alcohols; or one or more fatty amines or combinations thereof. The device can be administered to a subject in need thereof an effective amount of one or more active agents. The at least one biocompatible polymer may be selected from the group comprising poly ethylene-vinyl-acetate, vinyl acetate, silicone, polycaprolactone, polylacticco-glycolic acid, polylactic acid or polyglycolic acid.

The invention provides a device comprising: at least one biocompatible polymer, and an eutectic composition comprising a first agent and an agent capable of forming a eutectic composition with the first agent; or one or more fatty acids; or one or more fatty alcohols; or one or more fatty amines or combinations thereof. The device can be administered to a subject in need thereof an effective amount of one or more active agents. The at least one biocompatible polymer may be selected from the group comprising poly ethylene-vinyl-acetate, vinyl acetate, silicone, polycaprolactone, polylacticco-glycolic acid, polylactic acid or polyglycolic acid.

A novel AI-driven drug-repurposing method, DeepDrug, is used to identify a lead combination of previously FDA-approved drugs to treat AD by targeting the upstream genetic markers along the AD pathology. A three-step methodology is used. First, a heterogeneous biomedical graph is constructed comprising complex and interconnected genes, proteins, and drug information to capture the network characteristics of the AD pathology, considering the expert known associations between different AD pathways and utilizing node weighting and edge weighting and direction. Second, the curated graph is taken as an input to an artificial intelligence (AI)-driven graphical neural network (GNN) framework, with embeddings of drug and gene nodes as the outputs. Third, a drug scoring and selection analysis is conduced to generate the drug-gene scores and identify a lead combination of repurposed AD drug candidates for clinical verification.