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This invention relates to a novel mouse model that permits temporal and spatial inactivation of the oxytocin receptor. Oxytocin is a neurohormone that has been associated with human diseases such as autism and schizophrenia. The use of animal models to study oxytocin disease progression has been invaluable. However, existing mouse models have been limited to knockouts which leads to early mortality. Researchers at the National Institute of Mental Health (NIMH) generated the conditional oxytocin receptor knockout mice using the Cre-loxP and FLP-FRT systems.

Topisomerases are cellular enzymes that are vital for replication of the genome. However, if topisomerase and DNA form covalent complexes that prevent the resealing of DNA, this may lead to cell death. Essentially, this invention consists of a new isolated and cloned enzyme, tyrosyl-DNA phospodiesterase (TDP1) that is capable of hydrolyzing the covalent complexes between topisomerase and DNA, allowing the DNA to reseal.

Available for licensing are new methods of rapidly treating depression. The drugs currently used to treat depression work by increasing the activity at serotonin, norepinephrine and perhaps dopamine receptors in the CNS. However these drugs are effective in only 60-70% of patients, require 3-4 weeks of treatment before clinical improvement and have many side effects. These inventors have shown that in human patients, the administration of anti-muscarinic agents produces a rapid, prolonged alleviation of depressive symptoms.

Serotonin is an important modulator of many developmental, behavioral, and physiological processes, and it has been implicated in depression, anxiety, schizophrenia, obsessive compulsive disorders, and substance abuse. Serotonin’s pharmacology is extremely complex and it is mediated by seven of serotonin receptor subtypes and it is present in several tissues. Although it has been a subject of a number of studies, its role has been difficult to ascertain. To investigate the role of serotonin in these disorders, the murine gene was disrupted by homologous recombination.

Gene therapy and gene transfer have recently been recognized as effective therapeutic tools to combat diseases. Accordingly, market demands for vectors and carriers to facilitate such interventions have surged in recent years. Retroviral vectors provide an efficient and safe means of gene transfer to eukaryotic cells. The present invention relates to genetic engineering involving retrovirus packaging cells that produce retroviral vectors.

The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of autoimmune diseases and T cell malignancies. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. The toxin portion of the immunotoxin is genetically engineered to maintain bioactivity when recombinantly produced in Pichia pastoris.

The invention concerns immunotoxins and methods of using the immunotoxins for the treatment of rejection response in a patient, including graft-versus-host disease and transplantation of organs, tissues and cells into a host. In a specific embodiment of the invention, the transplant involves pancreatic islet cells. The immunotoxins are targeted via an antibody that is specific to T cells. This allows the specific ablation of resting T cells, resulting in an accentuation of immune tolerizing responses and an increased tolerance to transplants and grafts.

The invention concerns immunotoxins and methods of making the immunotoxins. Targeting of the immunotoxins occurs via an antibody that is specific to T cells. This allows the specific ablation of malignant T cells and resting T cells. The transient ablation of resting T cells can "reset" the immune system by accentuating tolerizing responses. As a result, the immunotoxin can be used to treat autoimmune disease, malignant T cell-related cancers, and graft-versus-host disease.

NIH inventors, in collaboration with Scott and White Memorial Hospital inventors, have developed new immunotoxins comprising a mutant diphtheria toxin linked to an anti-prostate specific membrane antigen (PSMA) fold-back diabody. The fold-back diabody construct has a shortened linker region between the heavy and light chains of the antibody variable domain. This construct allows interactions between the longer-linked variable domains while preventing interactions between the shorter-linked variable domains.