Imaging in drug development with reporter mice

Drug development is a time consuming and costly process, and new molecules go through preclinical studies in a variety of experimental animals and different phases of clinical trials before the drug's developers apply for the Food and Drug Administration's approval. The arsenal of detection devices, identified biomarkers, labeled drugs, genetically encoded reporters and animal models is rapidly expanding, providing new approaches for pharmacokinetic and pharmacodynamic studies. In this scenario, molecular and functional imaging techniques can be very attractive, in that if applied since the initial stages of drug development can provide evidences of activity or unexpected toxicity, confirm the effect occurring on a specific target of new chemical entities and identify patients who are more likely to benefit, thus stopping earlier non promising projects and investing more time and money on specific promising ones, reducing the total cost and risk of drug development. in this review article the major strategies in which molecular imaging techniques are helping pharmacological research are reported. The approach choice, the features of the reporter animal, the imaging technique and the reporter gene are discussed evaluating pros and cons of drug labelling and of the use of animals, that express a reporter gene in any phase of the drug development process

Integrative proteome and transcriptome analysis of extramedullary erythropoiesis and its reversal by transferrin treatment in a mouse model of Beta-thalassemia

Beta-thalassemia results from mutations of the β-hemoglobin (Hbb) gene and reduced functional Hbb synthesis. Excess α-Hb causes globin chain aggregation, oxidation, cytoskeletal damage, and increased red blood cell clearance. These events result in anemia, altered iron homeostasis, and expansion of extramedullary erythropoiesis. Serum transferrin (Tf) is suggested to be an important regulator of erythropoiesis in murine models of thalassemia. The present study was conducted to establish a quantitative proteomic and transcriptomic analysis of transferrin-modulated extramedullary erythropoiesis in the spleen of wild type and thalassemic Hbb(th3/+) mice. Our LC-MS/MS protein analysis and mRNA sequencing data provide quantitative expression estimates of 1590 proteins and 24 581 transcripts of the murine spleen and characterize key processes of erythropoiesis and RBC homeostasis such as the whole heme synthesis pathway as well as critical components of the red blood cell antioxidant systems and the proliferative cell cycling pathway. The data confirm that Tf treatment of nontransfused Hbb(th3/+) mice induces a systematic correction of these processes at a molecular level. Tf treatment of Hbb(th3/+) mice for 60 days leads to a complete molecular restoration of the normal murine spleen phenotype. These findings support further investigation of plasma-derived Tf as a treatment for thalassemia