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This technology includes lentivirus vectors to be used to treat sickle cell disease and beta thalassemia. (i) Lin28A or Lin28B vectors designed for erythroid-specific expression using EKLF1, SPTA1, or similar erythroid-specific regulatory elements will be used to transduce hematopoietic stem cells isolated from humans with sickle cell disease or beta-thalassemia syndromes.

This technology includes transgenic mice in which designer rat M3 muscarinic receptor mutants were expressed only in islet 13-cells (directed by rat insulin promoter II), were unable to bind acetylcholine (the endogenous ligand) but could be selectively activated by an otherwise pharmacologically inert compound (clozapine-N-oxide (CNO)). The R-q receptor contained a Y148C point mutation, which enabled CNO to selectively activate G proteins of the Gq/11 family. The R-5 receptor contained an A238G mutation, which enabled CNO to selectively activate G proteins of the G5 family.

This technology includes identification of the wild mouse microbiome as a method to increase resistance to lethal viral infection. We establish that the gut microbiome of barrier-raised C57BL/6 mice is dysbiotic compared to that of their outbred, wild-living progenitors, Mus musculus domesticus. We find that the multigenerational offspring of pregnant germfree C57BL/6 mice reconstituted with the gut microbiome of wild mice exhibit a less inflammatory response and increased survival following influenza A virus infection.

Local inflammation processes are crucially important in the host defense against pathogens and for successful immunization because proinflammatory cytokines are necessary for initiation and propagation of an immune response. However, normal inflammatory responses are eventually terminated by physiological termination mechanisms, thereby limiting the strength and duration of immune responses, especially to weak antigens. The inventors have shown that adenosine A2a and A3a receptors play a critical role in down-regulation of inflammation in vivo.

Patient conditioning is a critical initial step in hematopoietic stem and progenitor cell (HSPC) transplantation procedures to enable marrow engraftment of infused cells. Conditioning regimens have traditionally been achieved by delivering cytotoxic doses of chemotherapeutic agents and radiation. However, these regimens are associated with significant morbidity and mortality, and cannot be used safely in elderly or subjects with comorbidities.

This technology includes a strategy to target tumor cells that lost antigen following reaction with a therapeutic antibody by targeting the complement component C3d that has been deposited on target cells by the primary antibody. We previously generated a C3d-specific mouse/human chimeric antibody called C8xi and obtained proof of principle for the approach in two preclinical models. Here we summarize the generation of a new set of C3d targeting antibodies.

Adeno-associated virus (AAV) is being developed for gene therapy applications. This virus type presents several advantages over alternate vectors for therapeutic gene delivery. AAV is not considered pathogenic and transduces stably dividing and non-dividing cells. AAV also shows good serotype specificity to various cell types for targeted gene delivery.

To date there have been no adequate methods to determine the frequency of mutations in humans. This invention discloses a method of measuring the mutational frequency of a mitochondrial DNA sequence by sequencing mitochondrial DNA from clonally expanded single cells such as CD34+ human stem cells. Sequencing for mitochondrial DNA polymorphisms and mutations may also be useful as a general method to detect minimal residual disease in leukemia. The mitochondrial genome is particularly susceptible to mutations and these may be used to measure genomic mutagenesis by virtue of comparison.

This invention portrays a simple method for treatment of antigen-deficiency diseases by orally administering to a subject a therapeutically effective amount of the deficient antigen, wherein the antigen is not present in a liposome. This method increases hemostasis in a subject having hemophilia A or B, by orally administering to the hemophiliac a therapeutically effective amount of the appropriate clotting factor, sufficient to induce oral tolerance and supply exogenous clotting factor to the subject.

This mouse has been generated by targeted gene disruption. The mouse provides a model to investigate the function of the chemokine receptor CX3CR1, which is a proinflammatory receptor for the leukocyte chemoattractant CX3CL1 (aka fractalkine). As an example, the mouse is in use in the study of atherosclerosis. Further, the mouse may serve as a model study the role of the immune system during infection with pathogens as well as other immunologically mediated diseases and responses to tumors.