We targeted the gene in rat SSCs with TALENs and transplanted these deficient SSCs into sterile recipients. mouse models of human malignancy have paved the way for studying malignancy biology, genomics, effects on cancer growth kinetics, propensity for metastasis, and treatment response. A plethora of genetically immunodeficient mouse models, with varying immune phenotypes, exist for such studies(10). However, drug efficacy testing and downstream analysis such as pharmacokinetic (PK) / pharmacodynamic (PD) studies are limited because of inconsistent or poor tumor engraftment, high variability in tumor growth kinetics and limited tumor growth potential. As a result, a significantly large number of mice are used for drug efficacy screening Rabbit Polyclonal to OR2B6 in order to achieve a cohort of animals with tumors of comparable size and comparable tumor growth AKOS B018304 kinetics for treatment. We explored whether these cell AKOS B018304 lines might grow more consistently in a versatile in vivo model such as the immunodeficient rat. The laboratory rat remains the favored species for toxicology research because of its relative physiological similarity to humans (11C14). The metabolism and pharmacokinetic properties of drugs in rats is similar to humans compared to mice. All toxicology and safety profiling of drugs is performed in rats while efficacy studies are conducted primarily in mice models due to a lack of appropriate SCID-rat models. Data quality for drug development would be much improved if all the relevant data sets are generated in the same model. Due to the large size of the rats, tumors can be produced to nearly ten times the volume (or double the diameter) allowed in the mouse (15, 16). Rats have ten occasions the blood volume of mice. Therefore, AKOS B018304 rats can accommodate multiple blood samplings from the same test animal at different time points for blood cancer efficacy assessment, clinical pathology profiling, and pharmacokinetic sampling. Since the rat is the favored model for toxicology and safety testing, a rat with human cancer would allow for a combination of chemotherapy efficacy, pharmacokinetic and preliminary toxicology testing all in one animal thereby greatly reducing the number of animals needed while improving the quality of data generated. In order to generate cancer xenograft models or humanize a tissue in the rodent by replacing endogenous cells with human cells or ectopically transplanting human tissues, the animal must be immunodeficient to inhibit rejection of the xenogeneic cells. While many immunodeficient mouse models exist with differing capabilities for accepting human cells (10), very few rat models can engraft human cells (17, 18). The nude rat (RNU; NIH-TALE Nuclease (XTN) to create a mutation in (Recombination Activating Gene 2) which is critical for V(D)J recombination and its deletion disrupts maturation of B and T cells of the immune system (31, 32). Rat spermatogonial stem cells (SSCs) were targeted, which have recently been described as an alternative to genetic manipulation of embryos in rats (33). These altered SSCs can assimilate into the testes of sterile males and give rise to normal offspring, allowing germline transmission of the genetic modification of interest in one generation. Here we report the generation of AKOS B018304 a Sprague-Dawley knockout (SDR) rat characterized by a loss of mature B cells and severely reduced T cells compared with wild-type AKOS B018304 Sprague Dawley rats. We demonstrate.
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