Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human growth hormone (hGH) deficiency causes retarded growth and abnormalities in body fat distribution and abundance, muscle growth, and bone mineralization. While injection of recombinant hGH may reverse or ameliorate symptoms of deficiency, therapy aiming at in vivo synthesis of hGH is still of considerable clinical interest. Hydrodynamic injection of a simple plasmid vector containing a human ubiquitin promotor and the hGH gene were found to result in high and prolonged expression. Synthesis of hGH was achieved both in NOD/SCID mice and in three different inbred strains of immune competent mice. Although hGH antibodies were produced in immunocompetent mice, physiological effects of the protein were documented by increase in body weight, increased serum levels of insulin-like growth factor I and relative increased weight of the internal organs. Nonviral gene therapy may be regarded as a potential future way of reconstituting hGH expression in deficient individuals.
J Mol Med (Berl) 2002 Oct
PMID:Physiological effects of human growth hormone produced after hydrodynamic gene transfer of a plasmid vector containing the human ubiquitin promotor. 1239 51

A major challenge in gene therapy is to achieve efficient transduction of hematopoietic stem cells (HSC). It has previously been shown that lentiviral vectors (LV) transduce efficiently human cord blood-derived NOD/SCID mouse repopulating cells (SRC). Here we studied the effect of cytokines during the short ex vivo incubation with vector. Although SRC transduction was efficient without stimulation, the presence of cytokines significantly improved it. The treatment did not affect the engraftment level or the SRC frequency, but seemed to enhance SRC susceptibility to LV. SRC transduced in both conditions repopulated primary and secondary recipients, maintaining stable multi-lineage transgene expression. Using linear amplification-mediated PCR, we then analyzed vector integration in the bone marrow and CFC of the engrafted mice to monitor the clonal activity of the transduced SRC in vivo. We showed polyclonal engraftment, multi-lineage differentiation, and propagation to secondary recipients of individual SRC. We observed multiple integrations in most clones. These results provide the first formal demonstration that primitive human HSC with self-renewal and multi-lineage repopulation capacities were transduced by LV. Our findings are relevant for the design of clinical protocols that exploit this system to reach significant engraftment by genetically modified HSC in the absence of in vivo selection or strong conditioning regimens.
Mol Ther 2002 Nov
PMID:Molecular evidence of lentiviral vector-mediated gene transfer into human self-renewing, multi-potent, long-term NOD/SCID repopulating hematopoietic cells. 1240 60

An 18-month-old boy with severe combined immunodeficiency (SCID) due to an IL2-y-receptor defect had a successful engraftment following a related mismatched allogenic bone transplant. He subsequently developed post-transplantation lymphoproliferative disorder, with severe respiratory infection which resulted in death. The case presentation is followed by a discussion with differential diagnosis of the clinical findings, and then by a discussion of the pathology found and the implications of this diagnosis.
Pediatr Pathol Mol Med
PMID:Clinico-pathologic conference: 18-month old boy with fever and severe respiratory infection. 1242 4

Adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) was the first inherited disease treated with gene therapy. The pilot gene therapy studies demonstrated the safety, therapeutic potential and limitations of ADA gene transfer into hematopoietic cells using retroviral vectors. This review describes the latest progress in ADA-SCID dinical trials using peripheral blood lymphocytes (PBLs) and hematopoietic stem cells (HSCs). PBL gene therapy was able to restore T-cell functions after discontinuation of ADA enzyme replacement therapy, but only partially corrected the purine metabolic defect. The development of improved HSC gene transfer protocols, combined with low intensity conditioning, allowed full correction of the immunological and metabolic ADA defects, with clinic benefit. These results have important implications for future applications of gene therapy in other disorders involving the hemapoietic system.
Curr Opin Mol Ther 2002 Oct
PMID:Advances in gene therapy for ADA-deficient SCID. 1243 54

Effective suppression of HIV-1 replication requires inhibition of critical viral target molecules. Tat and Rev are indispensable regulatory factors for HIV-1 replication, whereas Env mediates virus entry by direct interaction with surface receptor CD4 and coreceptor CCR5 or CXCR4. Anti-HIV-1 tat-rev and env ribozymes and Rev aptamers were previously demonstrated to provide relatively long-term protection against HIV-1 infection in vitro. However, further improvements in these constructs for clinical application in a stem-cell-based gene therapy setting requires in vivo characterization. Toward this end, we introduced these constructs into CD34(+) hematopoietic progenitor cells by retrovirus-mediated gene transduction. Ribozyme- and aptamer-transduced CD34(+) cells differentiated normally into multiple lineages of erythroid and myeloid progenies in a colony-forming unit assay. Macrophages that differentiated from the transduced CD34(+) cells expressed anti-tat-rev and -env ribozymes and Rev aptamers and displayed their normal characteristic surface markers CD14, CD4, and CCR5. Using the SCID-hu mouse in vivo human thymopoiesis model, we demonstrated that ribozyme- and aptamer-transduced CD34(+) cells retained their normal capacity to reconstitute human fetal thymus and liver tissue (thy/liv) grafts. Reconstitution by ribozyme- and aptamer-transduced CD34(+) cells reached levels of up to 87% based on HLA surface marker staining. Differentiated thymocytes derived from reconstituted grafts expressed anti-tat-rev and -env ribozymes and Rev aptamers and showed significant resistance to HIV-1 infection upon challenge. Analysis of reconstituted thymocytes by hybridization revealed an average of 0.4 to 2 copies of vector sequences per cell. Southern analysis of proviral integration junctions in progeny thymocytes demonstrated that the human thy/liv grafts were reconstituted by a few primitive hematopoietic stem cells. These results highlight the utility of RNA-based anti-HIV-1 gene therapeutic approaches and their preclinical testing in a surrogate animal model harboring human tissue.
Mol Ther 2002 Dec
PMID:RNA-based anti-HIV-1 gene therapeutic constructs in SCID-hu mouse model. 1249 73

Radiosensitive severe combined immune deficiency in humans results from mutations in Artemis, a protein which, when coupled with DNA-dependent protein kinase catalytic subunit (DNA-PKcs), possesses DNA hairpin-opening activity in vitro. Here, we report that Artemis-deficient mice have an overall phenotype similar to that of DNA-PKcs-deficient mice-including severe combined immunodeficiency associated with defects in opening and joining V(D)J coding hairpin ends and increased cellular ionizing radiation sensitivity. While these findings strongly support the notion that Artemis functions with DNA-PKcs in a subset of NHEJ functions, differences between Artemis- and DNA-PKcs-deficient phenotypes, most notably decreased fidelity of V(D)J signal sequence joining in DNA-PKcs-deficient but not Artemis-deficient fibroblasts, suggest additional functions for DNA-PKcs. Finally, Artemis deficiency leads to chromosomal instability in fibroblasts, demonstrating that Artemis functions as a genomic caretaker.
Mol Cell 2002 Dec
PMID:Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. 1250 13

Because metabolic changes induced by chemotherapy precede the morphological changes, fluorine-18 fluorodeoxyglucose positron emission tomography ([(18)F]FDG PET) is thought to predict response to therapy earlier and more accurately than other modalities. To be a reliable predictor of response, changes in tumour [(18)F]FDG uptake should reflect changes in viable cell fraction, but little is known about the contribution of apoptotic and necrotic cancer cells and inflammatory tissue to the [(18)F]FDG signal. In a tumour mouse model we investigated the relation between chemotherapy-induced changes in various tumoral components and tumour uptake and size. SCID mice were subcutaneously inoculated in the right thigh with 5 x 10(6) Daudi cells. When the tumour measured 15-20 mm, Endoxan was given intravenously. At different time points [1-15 days (d1-d15) after the injection of Endoxan], ex vivo autoradiography and histopathology were performed in two mice and [(18)F]FDG uptake in the tumour and tumour size were correlated with the different cell fractions measured with flow cytometry in five mice. At d1/d3, similar reductions in [(18)F]FDG uptake and viable tumoral cell fraction were observed and these reductions preceded changes in tumour size. By d8/d10, [(18)F]FDG uptake had stabilised despite a further reduction in viable tumoral cell fraction. At these time points a major inflammatory response was observed. At d15, an increase in viable tumour cells was again observed and this was accurately predicted by an increase in [(18)F]FDG uptake, while the tumour volume remained unchanged. In contrast with variations in tumour volume, [(18)F]FDG is a good marker for chemotherapy response monitoring. However, optimal timing seems crucial since a transient increase in stromal reaction may result in overestimation of the fraction of viable cells.
Eur J Nucl Med Mol Imaging 2003 May
PMID:[(18)F]FDG PET monitoring of tumour response to chemotherapy: does [(18)F]FDG uptake correlate with the viable tumour cell fraction? 1260 98

We have investigated the influence of Ki-ras oncogene on Met/hepatocyte growth factor (HGF) receptor signaling in human carcinoma cells. The model system used in these studies included the DLD-1 colon cancer cell line with a mutated Ki-ras allele, and the DKO-4 cell line generated from DLD-1, with its mutant Ki-ras allele inactivated by targeted disruption. These cell lines were transduced with cDNAs of either active Met receptor or dominant negative Met receptor. As compared to the DLD-1 cells, constitutive overexpression of Met receptor in this cell line (DLD-1-Met) resulted in increased tumorigenicity in SCID mice. In contrast, overexpression of Met in DKO-4 cells (DKO-4-Met) that have lost oncogenic Ras activity demonstrated suppressed tumorigenicity with respect to the parent DKO-4 cell line. Tumors formed by the DLD-1-Met cells showed increased levels of mitogen-activated protein kinase (MAPK) and lower levels of apoptosis compared to the DKO-4-Met tumors. Overexpression of the dominant negative Met receptor cDNA decreased the Met phosphorylation levels in both DLD-1 and DKO-4 cells, but only suppressed tumorigenicity in the DKO-4 cell line. In vitro, HGF stimulation of DLD-1 cells resulted in a prolonged duration of MAPK activation, while DKO-4 cells exhibited a rapid attenuation of MAPK phosphorylation. The results suggest that Ki-ras mutations and HGF signaling cooperate to enhance tumor growth by increased duration of MAPK activation and decreased apoptosis in human carcinoma cells.
Mol Cancer Res 2003 Mar
PMID:Met receptor overexpression and oncogenic Ki-ras mutation cooperate to enhance tumorigenicity of colon cancer cells in vivo. 1265 12

There have been reports of successful follicular growth following xenogenic transplantation of the human ovarian cortex into immunodeficient mice. In this study, we examined the immunohistochemical expression and localization of steroidogenic enzymes in the graft of nonpathological human ovary following xenogenic transplantation into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. We studied human follicles following xenotransplantation into NOD-SCID mice using immunohistochemistry antibodies against the cell proliferation marker (Ki 67), steroidogenic enzymes P450 cholesterol side chain cleavage (P450 scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), cytochrome P450 17alpha hydroxylase (P450 c17), cytochrome P450 aromatase (P450 arom), androgen receptor (AR), estrogen receptor (ER), and Ad4-binding protein (Ad4BP), a transcription factor for all steroidogenic P450 genes. In the pre-antral follicles of these grafts, Ki 67 and Ad4BP were detected in both the theca and granulosa cell layer. P450 scc, P450 c17, 3beta-HSD, and AR were present in only the theca cell layer, observations of which were consistent with the findings of nonpathological human ovarian cortex. P450 arom and ER were not detected in these grafts, however, and these follicles did not possess any specific feature of a dominant follicle. These findings suggest that the expression of steroidogenic enzymes in human follicles following xenogenic transplantation into NOD-SCID mice is similar to that of nonpathological human ovaries. However, these follicles do not possess any features of dominant follicles, which are known to develop into the corpus luteum.
Mol Reprod Dev 2003 May
PMID:Immunohistochemical localization of steroidogenic enzymes in human follicle following xenotransplantation of the human ovarian cortex into NOD-SCID mice. 1265 35

X-linked adrenoleukodystrophy (ALD), an inherited demyelinating disorder of the central nervous system, can be corrected by allogeneic bone marrow transplantation, likely due to the turnover of brain macrophages that are bone marrow derived. ALD is characterized by an accumulation of very long chain fatty acids (VLCFA) due to the deficiency of an ATP binding cassette transporter that imports these fatty acids in peroxisomes. Murine retroviral transduction results in metabolic correction of ALD CD34(+) cells in vitro but reinfusion of these cells into ALD patients would not provide clinical benefit owing to the absence of selective advantage conferred by transgene expression. High-efficiency transduction of ALD CD34(+) peripheral blood mobilized cells was achieved using an HIV-based vector driving ALD gene expression under the elongation factor 1 alpha promoter and a protocol without prestimulation of CD34(+) cells with cytokines prior to transduction to preserve their stem cell properties. Efficient expression of the ALD gene was demonstrated in monocytes/macrophages derived from cultures of transduced ALD CD34(+) cells and in long-term culture initiating cells. VLCFA metabolism was corrected in transduced CD34(+), CFU-derived, and LTC-derived cells, indicating that the vector-encoded ALD protein was fully functional. Transplantation of transduced ALD CD34(+) cells into NOD/SCID mice resulted in long-term expression of ALD protein in monocytes/macrophages derived from engrafted stem cells.
Mol Ther 2003 Mar
PMID:Transduced CD34+ cells from adrenoleukodystrophy patients with HIV-derived vector mediate long-term engraftment of NOD/SCID mice. 1266 27


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