Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent published data have shown the efficacy of gene therapy treatments of certain monogenic diseases. Risks of insertional oncogenesis, however, indicate the necessity of developing new vectors with weaker or cell-restricted promoters to minimize the trans-activation activity of integrated proviruses. We have inserted the proximal promoter of the vav proto-oncogene into self-inactivating lentiviral vectors (vav-LVs) and investigated the expression pattern and therapeutic efficacy of these vectors. Compared with other LVs frequently used in gene therapy, vav-LVs mediated a weak, though homogeneous and stable, expression in in vitro-cultured cells. Transplantation experiments using transduced mouse bone marrow and human CD34(+) cells confirmed the stable activity of the promoter in vivo. To investigate whether the weak activity of this promoter was compatible with a therapeutic effect, a LV expressing the Fanconi anemia A (FANCA) gene was constructed (vav-FANCA LV). Although this vector induced a low expression of FANCA, compared to the expression induced by a LV harboring the spleen focus-forming virus (SFFV) promoter, the two vectors corrected the phenotype of cells from a patient with FA-A with the same efficacy. We propose that self-inactivating vectors harboring weak promoters, such as the vav promoter, will improve the safety of gene therapy and will be of particular interest for the treatment of diseases where a high expression of the transgene is not required.
 ...
PMID:Characteristics of lentiviral vectors harboring the proximal promoter of the vav proto-oncogene: a weak and efficient promoter for gene therapy. 1753 66

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, dysplasia, and a propensity for transformation to acute myeloid leukemia (AML). A wide spectrum of genetic aberrations has been associated with MDS, including chromosomal translocations involving the NUP98 gene, most commonly leading to fusions of NUP98 with abd-b group HOX genes, including HOXD13. We used vav regulatory elements to direct expression of a NUP98-HOXD13 (NHD13) fusion gene in hematopoietic tissues. NHD13 transgenic mice faithfully recapitulate all the key features of MDS, including peripheral blood cytopenias, bone marrow dysplasia and apoptosis, and transformation to acute leukemia. The MDS that develops in NHD13 transgenic mice is highly lethal; within 14 months, 90% of the mice died of either leukemic transformation or severe anemia and leukopenia due to progressive MDS. These mice provide a preclinical model that can be used for the evaluation of MDS therapy and biology.
 ...
PMID:NUP98-HOX translocations lead to myelodysplastic syndrome in mice and men. 1864 6

Fanconi anemia (FA) is an inherited genetic disease characterized mainly by bone marrow failure and cancer predisposition. Although gene therapy may constitute a good therapeutic option for many patients with FA, none of the clinical trials so far developed has improved the clinical status of these patients. We have proposed strategies for the genetic correction of bone marrow grafts from patients with FA, using lentiviral vectors (LVs). Here we investigate the relevance of the expression of FANCA to confer a therapeutic effect in cells from patients with FA-A, the most frequent complementation group in FA. Our data show that relatively weak promoters such as the vav or phosphoglycerate kinase (PGK) promoter confer, per copy of FANCA, physiological levels of FANCA mRNA in lymphoblastoid cell lines, whereas the cytomegalovirus and, more significantly, spleen focus-forming virus (SFFV) promoters mediated the expression of supraphysiological levels of FANCA mRNA. Insertion of the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) or a mutated WPRE into the 3' region of PGK-FANCA LVs significantly increased FANCA mRNA levels. At the protein level, however, all tested vectors conferred, per copy of FANCA, similar and physiological levels of the protein, except SFFV LVs, which again conferred supraphysiological levels of FANCA. In spite of their different activity, all tested vectors mediated a similar phenotypic correction in FA-A lymphoblastoid cell lines and also in hematopoietic progenitors from patients with FA-A. On the basis of the efficacy and safety properties of PGK LVs, a PGK LV carrying FANCA and a mutant WPRE is proposed as an optimized vector for the gene therapy of patients with FA-A.
 ...
PMID:Development of lentiviral vectors with optimized transcriptional activity for the gene therapy of patients with Fanconi anemia. 2000 54