Annals of the New York Academy of Sciences
-
Ann. N. Y. Acad. Sci. · May 2005
ReviewThe miniature pig as an animal model in biomedical research.
Crucial prerequisites for the development of safe preclinical protocols in biomedical research are suitable animal models that would allow for human-related validation of valuable research information gathered from experimentation with lower mammals. In this sense, the miniature pig, sharing many physiological similarities with humans, offers several breeding and handling advantages (when compared to non-human primates), making it an optimal species for preclinical experimentation. The present review offers several examples taken from current research in the hope of convincing the reader that the porcine animal model has gained massively in importance in biomedical research during the last few years. The adduced examples are taken from the following fields of investigation: (a) the physiology of reproduction, where pig oocytes are being used to study chromosomal abnormalities (aneuploidy) in the adult human oocyte; (b) the generation of suitable organs for xenotransplantation using transgene expression in pig tissues; (c) the skin physiology and the treatment of skin defects using cell therapy-based approaches that take advantage of similarities between pig and human epidermis; and (d) neurotransplantation using porcine neural stem cells grafted into inbred miniature pigs as an alternative model to non-human primates xenografted with human cells.
-
Ann. N. Y. Acad. Sci. · Jan 2005
ReviewProgress toward the genetic treatment of the beta-thalassemias.
The beta-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the beta-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated beta-globin gene in autologous HSCs is a highly attractive alternative treatment. ⋯ The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.
-
Ann. N. Y. Acad. Sci. · Jan 2005
ReviewSuccessful correction of the human Cooley's anemia beta-thalassemia major phenotype using a lentiviral vector flanked by the chicken hypersensitive site 4 chromatin insulator.
beta-Thalassemias are the most common single-gene disorders and are potentially amenable to gene therapy. While retroviral vectors carrying the human beta-globin cassette were notoriously unstable and expressed poorly, considerable progress has now been made using lentiviral vectors (LVs), which stably transmit the beta-globin expression cassette. Mouse studies using LVs have shown correction of the beta-thalassemia-intermedia phenotype and a partial, variable correction of the mouse beta-thalassemia major phenotype, despite the use of beta-globin-hypersensitive sites that are known to result in position-independent effects. ⋯ The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3-4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal control subjects. Results show genetic correction of primitive human progenitor cells and normalization of the human thalassemia major phenotype.
-
Ann. N. Y. Acad. Sci. · Dec 2004
ReviewCost-effective violence prevention through targeted family interventions.
Efforts in violence prevention can focus on individual youth, their families, their schools, or the communities in which they live. Among the small number of program models that have been proven effective in repeated replications, those that focus on improving family management and child care have been found to be the most cost-effective. ⋯ All of these programs involve detailed protocols, extensive staff training and supervision, and quality-assurance procedures. The factors limiting their wider adoption include staff resistance to their structured approach, cost-sharing issues between local and state levels of government, and the political power of existing programs.
-
Ann. N. Y. Acad. Sci. · Oct 2004
ReviewPharmacological characterization of nociceptin/orphanin FQ receptors, a novel opioid receptor family, in the midbrain periaqueductal gray.
A fourth opioid receptor family was cloned and named after its endogenous ligand as nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor. We have characterized several NOP receptor ligands pharmacologically at native NOP receptors of ventrolateral periaqueductal gray (vlPAG) neurons by investigating their interactions with N/OFQ in activating G protein-coupled inwardly rectifying K+ (GIRK) channels. ⋯ In Ro 64-6198-unresponsive neurons, N/OFQ activated GIRK channels through NOP receptors. (6) Nocistatin, a functional antagonist of N/OFQ in the spinal cord, did not affect the effect of N/OFQ in most of the recorded neurons. Our functional studies of NOP receptor ligands at native brain NOP receptors reveal that some of them act differently from those at expressed receptors of cell cultures.