Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene therapy of severe hemoglobinopathies will require high-level expression of a transferred globin gene in erythroid cells. Distant regulatory elements flanking the beta-globin gene cluster, the locus control region, are needed for appropriate expression. We have explored the use of a human parvovirus, the adeno-associated virus (AAV), for globin gene transfer. The human A gamma-globin gene, linked to hypersensitivity site 2 from the locus control region of the beta-globin gene cluster, was subcloned into a plasmid (psub201) containing the AAV inverted terminal repeats. This construct was cotransfected with a helper plasmid containing trans-acting AAV genes into human 293 cells that had been infected with adenovirus. The recombinant AAV vector containing hypersensitivity site 2 stably introduced on average one or two unrearranged proviral copies into human K562 erythroleukemia cells. The transferred globin gene exhibited normal regulation upon hemin induction of erythroid maturation and was expressed at a level equivalent to a native chromosomal A gamma-globin gene.
 ...
PMID:Regulated high level expression of a human gamma-globin gene introduced into erythroid cells by an adeno-associated virus vector. 132 31

Towards a goal of using adeno-associated viruses (AAV), the human parvovirus, as the gene transfer vector for gene therapy of hemoglobinopathies, the human beta-globin (h beta G) cDNA was ligated downstream of the P40 promoter of AAV type 2 (AAV2) genome. Transfection via electroporation of the construct into human 293 cells (embryonal kidney cell line) resulted in expression of the cloned h beta G cDNA, as evidenced by the synthesis of transcripts hybridizable to h beta G probe. The transfection led to the recombinant genome to be excised out of the plasmid and replicate in the cell, followed by production of the recombinant AAV that harbors h beta G cDNA.
 ...
PMID:The recombinant human parvoviruses for gene therapy of hemoglobinopathies. 136 18

The past five years have seen numerous advances in the field of pediatric infectious diseases, and many of these have a substantial impact on the practice of dermatology. We review some of these advances and discuss their implications on etiology, diagnosis, therapy and complications of some relatively common conditions. The etiologic agent of exanthum subitum (roseola infantum) has been clearly implicated as a herpesvirus-6. Although in the classically described situation high fever in a young child is followed by defervescence and rash, two new scenarios have been described associated with this virus. The first is fever without rash and the second is rash without fever. The etiologic agent of erythema infectiosum ("slapped cheek") has been shown to be a human parvovirus B19. The virus has also been associated with aplastic crises (in hemoglobinopathies), hydrops fetalis, and a syndrome of subacute arthralgias in women. The etiologic agent in cat-scratch disease has recently been shown to be a small pleomorphic bacillus that also can produce pyogenic granuloma-like lesions in patients with acquired immunodeficiency syndrome. The number of cases of congenital syphilis, particularly in large cities, is increasing tremendously. Many of these infants have received no prenatal care because of drug abuse problems in their parents. Finally, we describe the changing etiology of impetigo that is predominantly associated with Staphylococcus aureus. We further describe the growing resistance to erythromycin and several new erythromycin drug-drug interactions.
 ...
PMID:Recent advances in pediatric infectious diseases and their impact on dermatology. 206 33

Life-threatening infections with Streptococcus pneumoniae and parvovirus occurred in two patients with hemoglobin S-beta-thalassemia. We recommend that acute febrile illnesses in the presence of any hemoglobinopathy be considered potentially life threatening, and managed accordingly.
 ...
PMID:Life-threatening infection in two children with hemoglobin S-beta-thalassemia. 756 4

The diverse manifestations of human parvovirus B19 infection have been well established. Erythema infectiosum, fetal hydrops, adult arthropathy, and aplastic anemia in patients with hemoglobinopathies or underlying immunocompromise have been described. Recently we successfully treated a patient who, after heart transplantation, had fever, rash, and pneumonia with respiratory failure caused by human parovirus B19. Human parovirus B19 has not been reported previously as a pathogen causing pulmonary disease after pediatric heart transplantation, and we wish to report it at this time.
 ...
PMID:Severe pneumonia after heart transplantation as a result of human parvovirus B19. 803 18

The pathogenic human parvovirus B19 is an autonomously replicating virus with a remarkable tropism for human erythroid progenitor cells. Although the target cell specificity for B19 infection has been suggested to be mediated by the erythrocyte P-antigen receptor (globoside), a number of nonerythroid cells that express this receptor are nonpermissive for B19 replication. To directly test the role of expression from the B19 promoter at map unit 6 (B19p6) in the erythroid cell specificity of B19, we constructed a recombinant adeno-associated virus 2 (AAV), in which the authentic AAV promoter at map unit 5 (AAVp5) was replaced by the B19p6 promoter. Although the wild-type (wt) AAV requires a helper virus for its optimal replication, we hypothesized that inserting the B19p6 promoter in a recombinant AAV would permit autonomous viral replication, but only in erythroid progenitor cells. In this report, we provide evidence that the B19p6 promoter is necessary and sufficient to impart autonomous replication competence and erythroid specificity to AAV in primary human hematopoietic progenitor cells. Thus, expression from the B19p6 promoter plays an important role in post-P-antigen receptor erythroid-cell specificity of parvovirus B19. The AAV-B19 hybrid vector system may also prove to be useful in potential gene therapy of human hemoglobinopathies.
 ...
PMID:Parvovirus B19 promoter at map unit 6 confers autonomous replication competence and erythroid specificity to adeno-associated virus 2 in primary human hematopoietic progenitor cells. 861 12

Anemia, mental status changes, and fatal respiratory failure complicated a febrile illness in a previously healthy 14-year-old black female. At autopsy, widespread fat emboli and bone marrow necrosis were found. Hemoglobin electrophoresis on an antemortem, pretransfusion specimen revealed hemoglobin S/beta+ thalassemia. Acute parvovirus B19 (PV B19) infection was suspected. Postmortem serum and a variety of paraffin-embedded tissues were assayed for PV B19 DNA using the polymerase chain reaction (PCR). The expected PCR product was identified in the serum specimen and in paraffin-embedded sections of bone marrow, kidney, spleen, parathyroid, thyroid, adrenal, and gastrointestinal tract: lung, liver, ovary, fallopian tube, uterus, brain, heart, and pancreas were negative. PV B19 infection is highly contagious and may be rapidly fatal in children with hemoglobinopathies by several mechanisms, including fat embolism. Therefore, there exists the risk of multiple deaths within a family. The acute infection may be easily and expeditiously diagnosed using serum or a variety of paraffin-embedded tissues.
 ...
PMID:Fatal fat embolism syndrome in a child with undiagnosed hemoglobin S/beta+ thalassemia: a complication of acute parvovirus B19 infection. 896 32

Adeno-associated virus type 2 (AAV), a nonpathogenic human parvovirus, is gaining attention as a vector for potential use in human gene therapy. We and others have described AAV-mediated beta-globin gene transfer and expression in established human and murine erythroleukemia cell lines in vitro. However, successful AAV-mediated globin gene transduction of hematopoietic stem cells and long-term expression in vivo in progeny cells have not been documented. We report here that infection of murine hematopoietic bone marrow cells ex vivo with a recombinant AAV vector containing the genomic copy of a normal human globin gene followed by transplantation of these cells into lethally irradiated congenic mice resulted in efficient gene transfer into hematopoietic cells with long-term repopulating ability as detected by the presence of the human globin gene sequences in bone marrow and spleen in primary recipient mice for at least 6 months. Long-term expression of the human globin gene was also detected in bone marrow, but not in spleen, in primary recipient mice. Furthermore, in secondary-transplant experiments, we were also able to document the presence as well as expression of the transduced human globin gene in mouse bone marrow for up to 3 months. These results provide further support for potential use of the AAV-based vector system in gene therapy of human hemoglobinopathies in general and sickle-cell anemia and beta-thalassemia in particular.
 ...
PMID:Adeno-associated virus type 2-mediated transduction of murine hematopoietic cells with long-term repopulating ability and sustained expression of a human globin gene in vivo. 906 Jun 72

Human parvovirus B19 gene expression from the viral p6 promoter (B19p6) is restricted to primary human hematopoietic cells undergoing erythroid differentiation. We have demonstrated that expression from this promoter does not occur in established human erythroid cell lines in the context of a recombinant parvovirus genome (Ponnazhagan et al. J Virol 69:8096-8101, 1995). However, abundant expression from this promoter can be readily detected in primary human bone marrow cells (Wang et al. Proc Natl Acad Sci USA 92:12416-12420, 1995; Ponnazhagan et al. J Gen Virol 77:1111-1122, 1996). In the present studies, we investigated the pattern of expression from the B19p6 promoter in primary human bone marrow-derived CD34+ HPC undergoing differentiation into myeloid and erythroid lineages. CD34+ cells were transduced with recombinant adeno-associated virus 2 (AAV) vectors containing the beta-galactosidase (lacZ) gene under the control of the following promoters/enhancers: the cytomegalovirus promoter (vCMVp-lacZ), B19p6 promoter (vB19p6-lacZ), B19p6 promoter with an upstream erythroid cell-specific enhancer element (HS-2) from the locus control region (LCR) from the human beta-globin gene cluster (vHS2-B19p6-lacZ), and the human beta-globin gene promoter with the HS-2 enhancer (vHS2-beta p-lacZ). Transgene expression was evaluated either 48 h after infection or following erythroid differentiation in vitro for 3 weeks. Whereas high-level expression from the CMV promoter 48 h after infection diminished with time, low-level expression from the B19p6 and the beta-globin promoters increased significantly following erythroid differentiation. Furthermore, in HPC assays, there was no significant difference in the level of expression from the CMV promoter in myeloid or erythroid cell-derived colonies. Expression from the B19p6 and the beta-globin promoters, on the other hand, was restricted to erythroid cell colonies. These data further corroborate that the B19p6 promoter is erythroid cell-specific and suggest that the recombinant AAV-B19 hybrid vectors may prove useful in gene therapy of human hemoglobinopathies in general and sickle cell anemia and beta-thalassemia in particular.
 ...
PMID:Adeno-associated virus 2-mediated transduction and erythroid lineage-restricted expression from parvovirus B19p6 promoter in primary human hematopoietic progenitor cells. 1064 62

With the advent of the era of International Space Station (ISS) and Mars exploration, it is important more than ever to develop means to cure genetic and acquired diseases, which include cancer and AIDS, for these diseases hamper human activities. Thus, our ultimate goal is to develop protocols for gene therapy, which are suitable to humans on the earth as well as in space. Specifically, we are trying to cure the hemoglobinopathies, beta-thalassemia (Cooley's anemia) and sickle cell anemia, by gene therapy. These well-characterized molecular diseases serve as models for developing ex vivo gene therapy, which would apply to other disorders as well. For example, the procedure may become directly relevant to treating astronauts for space-anemia, immune suppression and bone marrow derived tumors, e.g. leukemia. The adeno-associated virus serotype 2 (AAV2) is a non-pathogenic human parvovirus with broad host-range and tissue specificity. Exploiting these characteristics we have been developing protocols for recombinant AAV2 (rAAV)-based gene therapy. With the rAAV constructs and hematopoietic stem cell (HSC) culture systems in hand, we are currently attempting to cure the mouse model of beta-thalassemia [C57BL/6- Hbbth/Hbbth, Hb(d-minor)] by HSC transplantation (HST) as well as by gene therapy. This paper describes the current status of our rAAV-gene therapy research.
 ...
PMID:Developing protocols for recombinant adeno-associated virus-mediated gene therapy in space. 1269 49


1 2 3 Next >>