Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review addresses several questions in the light of the results recently obtained by a gene therapy trial for the treatment of X-linked severe combined immunodeficiency. This primary immunodeficiency, characterized by a complete absence of T and natural killer lymphocytes, appeared as a good model for the application of gene therapy, combining an expected selective advantage for transduced cells, an absence of immunological response to the vector and/or the therapeutic transgene together with accessibility to hematopoietic stem cells. After a brief description of the disease and its physiopathology we summarize the clinical results of the gene therapy trial putting them in perspective with those obtained following allogeneic hematopoietic stem cell transplantation. Definitive conclusions cannot be thrown due to the limited number of gene therapy-treated patients and their relatively short follow-up.
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PMID:Gene therapy of X-linked severe combined immunodeficiency. 1475 33

In the fifty years since Ogden Bruton discovered agammaglobulinemia, more than 100 additional immunodeficiency syndromes have been described. These disorders may involve one or more components of the immune system, including T, B, and NK lymphocytes; phagocytic cells; and complement proteins. Most are recessive traits, some of which are caused by mutations in genes on the X chromosome, others in genes on autosomal chromosomes. Until the past decade, there was little insight into the fundamental problems underlying a majority of these conditions. Many of the primary immunodeficiency diseases have now been mapped to specific chromosomal locations, and the fundamental biologic errors have been identified in more than 3 dozen. Within the past decade the molecular bases of 7 X-linked immunodeficiency disorders have been reported: X-linked immunodeficiency with Hyper IgM, X-linked lymphoproliferative disease, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency, the Wiskott-Aldrich syndrome, nuclear factor kappaB essential modulator (NEMO or IKKg), and the immune dysregulation polyendocrinopathy (IPEX) syndrome. The abnormal genes in X-linked chronic granulomatous disease (CGD) and properdin deficiency had been identified several years earlier. In addition, there are now many autosomal recessive immunodeficiencies for which the molecular bases have been discovered. These new advances will be reviewed, with particular emphasis on the pulmonary complications of some of these diseases. In some cases there are unique features of lung abnormalities in specific defects. Infections obviously account for most of these complications, but the host reaction to infection often leads to characteristic findings that can be helpful diagnostically. Finally, advances in treatment of the underlying diseases as well as their infectious complications will be covered.
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PMID:Pulmonary complications of primary immunodeficiencies. 1498 Feb 76

Several primary immunodeficiencies are under consideration for gene therapy approaches because of limitations of current standard treatment. Many primary immunodeficiencies are caused by defects in single genes expressed in blood cells; thus addition of a correct copy of the gene to hematopoietic stem cells (HSCs) can generate immune cells with restored function. HSCs can be removed from a patient, treated outside the body, and reinfused. In the last decade, significant improvements have been made in transferring genes by means of retroviruses to HSCs in vitro, and gene therapy trials for patients with X-linked severe combined immunodeficiency (XSCID) and adenosine deaminase-deficient severe combined immunodeficiency have restored immune competence. Gene therapy is actively being pursued in other immunodeficiency disorders, including chronic granulomatous disease and Wiskott-Aldrich syndrome. However, enthusiasm for the correction of XSCID by means of gene therapy has been tempered by the occurrence of 2 cases of leukemia in gene therapy recipients caused by insertion of the retroviral vector in or near the oncogene LMO2. The likelihood of retroviral insertional mutagenesis was estimated to be very low in the past on the basis of theoretic calculations and the absence of observed malignancies in animal studies and early clinical trials. Emerging new findings on retroviral integration both in the patients with XSCID and experimental animals now indicate that the insertion of retroviral sequences into the genome carries significant risk. Understanding the magnitude of risk is now a priority so that safety can be improved for future gene therapy clinical trials.
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PMID:Successes and risks of gene therapy in primary immunodeficiencies. 1510 Jun 60

Perinatal transmission prophylaxis has led to a significant reduction of vertical human immunodeficiency virus (HIV) infection. Antiretroviral drugs are being widely used before and during pregnancy, although these drugs can have possible adverse effects on the fetus and newborn. In this context, we report a unique case of X-linked severe combined immunodeficiency in a neonate vertically exposed to HIV.
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PMID:A novel mutation in the interleukin-2 receptor gamma gene as the cause of lymphopenia in a neonate vertically exposed to human immunodeficiency virus. 1570 55

The authors selected articles published in the literature from January 2004 through December 2004 that were relevant to the areas of basic and clinical immunology. Several articles explored the development of TH1 or TH2 response and the role of the monocyte-T cell interaction. Others were articles describing the action of drugs commonly used in asthma to inhibit cytokine responses and the anti-inflammatory role of nonimmune pulmonary cells present in the lung. Several reports show how dendritic cells are being developed as vehicles for DNA vaccines aimed at stimulating cellular responses, an advance of great importance for HIV researchers working on vaccines, who are concerned about the different ways HIV evades the immune response. Other publications described Toll-like receptors in diverse cells, including mast cells and CD4+ T cells, for the recognition of viruses and bacteria. In the area of clinical immunology, an updated classification for primary immunodeficiencies with more than 100 identified genes responsible for these diseases and the report on the second clinical trial of gene therapy for X-linked severe combined immunodeficiency syndrome were published. Significant advances included the clinical prognosis in common variable immunodeficiency for patients presenting with lung pathology, the safety of live vaccines in partial DiGeorge syndrome, the report of patients with complete DiGeorge syndrome with the presence of peripheral blood T cells, the clinical spectrum of patients with NF-kappaB essential modifier (NEMO) gene deficiency, the publication of a consensus algorithm for the management of hereditary angioedema, and the report of immune restoration syndrome in pediatric HIV infection.
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PMID:Basic and clinical immunology. 1608 98

X-linked severe combined immunodeficiency (XSCID) is characterized by profound immunodeficiency and early mortality, the only potential cure being hematopoietic stem cell (HSC) transplantation or gene therapy. Current clinical gene therapy protocols targeting HSCs are based upon ex vivo gene transfer, potentially limited by the adequacy of HSC harvest, transduction efficiencies of repopulating HSCs, and the potential loss of their engraftment potential during ex vivo culture. We demonstrate an important proof of principle by showing achievement of durable immune reconstitution in XSCID dogs following intravenous injection of concentrated RD114-pseudotyped retrovirus vector encoding the corrective gene, the interleukin-2 receptor gamma chain (gamma c). In 3 of 4 dogs treated, normalization of numbers and function of T cells were observed. Two long-term-surviving animals (16 and 18 months) showed significant marking of B lymphocytes and myeloid cells, normalization of IgG levels, and protective humoral immune response to immunization. There were no adverse effects from in vivo gene therapy, and in one dog that reached sexual maturity, sparing of gonadal tissue from gene transfer was demonstrated. This is the first demonstration that in vivo gene therapy targeting HSCs can restore both cellular and humoral immunity in a large-animal model of a fatal immunodeficiency.
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PMID:Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy. 1638 23

Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT.
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PMID:Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X-linked severe combined immunodeficiency. 1673 83

A retrovirus vector containing an enhanced green fluorescent protein complimentary DNA (EGFP cDNA) was used to mark and dynamically follow vector-expressing cells in the peripheral blood of bone marrow transplanted X-linked severe combined immunodeficient dogs. CD34(+) cells isolated from young normal dogs were transduced, using a 2 day protocol, with an amphotropic retroviral vector that expressed enhanced green fluorescent protein (EGFP) and the canine common gamma chain (gammac) cDNAs. Following transplantation of the transduced cells, normal donor peripheral blood lymphocytes (PBL) appeared by 1 month post-bone marrow transplant (BMT) and rescued three of five treated dogs from their lethal immunodeficiency. PCR and flow cytometric analysis of post-BMT PBL documented the peripheral EGFP expressing cells as CD3(+) T cells, which varied from 0% to 28%. Sorting of EGFP(+) and EGFP(-) peripheral blood T cells from two dogs, followed by vector PCR analysis, showed no evidence of vector shutdown. EGFP expression in B cells or monocytes was not detected. These marking experiments demonstrate that the transduction protocol did not abolish the lymphoid engraftment capability of ex vivo transduced canine CD34(+) cells and supports the potential utility of the MSCV retroviral vector for gene transfer to XSCID affected canine hematopoietic progenitor cells (HPC).
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PMID:Marking of peripheral T-lymphocytes by retroviral transduction and transplantation of CD34+ cells in a canine X-linked severe combined immunodeficiency model. 1744 4

A novel intrinsic HIV-1 antisense gene was previously described with RNA initiating from the region of an HIV-1 antisense initiator promoter element (HIVaINR). The antisense RNA is exactly complementary to HIV-1 sense RNA and capable of forming approximately 400 base-pair (bp) duplex RNA in the region of the long terminal repeat (LTR) spanning the beginning portion of TAR in the repeat (R) region and extending through the U3 region. Duplex or double-stranded RNA of several hundred nucleotides in length is a key initiating element of RNA interference (RNAi) in several species. This HIVaINR antisense RNA is also capable of forming multiple stem-loop or hairpin-like secondary structures by M-fold analysis, with at least one that perfectly fits the criteria for a microRNA (miRNA) precursor. MicroRNAs (miRNAs) interact in a sequence-specific manner with target messenger RNAs (mRNAs) to induce either cleavage of the message or impede translation. Human mRNA targets of the predicted HIVaINR antisense RNA (HAA) microRNAs include mRNA for the human interleukin-2 receptor gamma chain (IL-2RG), also called the common gamma (gammac) receptor chain, because it is an integral part of 6 receptors mediating interleukin signalling (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R and IL-21R). Other potential human mRNA targets include interleukin-15 (IL-15) mRNA, the fragile x mental retardation protein (FMRP) mRNA, and the IL-1 receptor-associated kinase 1 (IRAK1) mRNA, amongst others. Thus the proposed intrinsic HIVaINR antisense RNA microRNAs (HAAmiRNAs) of the human immunodeficiency virus form complementary targets with mRNAs of a key human gene in adaptive immunity, the IL-2Rgammac, in which genetic defects are known to cause an X-linked severe combined immunodeficiency syndrome (X-SCID), as well as mRNAs of genes important in innate immunity. A new model of intrinsic RNA silencing induced by the HIVaINR antisense RNA in the absence of Tat is proposed, with elements suggestive of both small interfering RNA (siRNA) and miRNA.
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PMID:RNA silencing and HIV: a hypothesis for the etiology of the severe combined immunodeficiency induced by the virus. 1878 56

The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in gammac-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing gammac from the phosphoglycerate kinase (PGK) and Wiscott-Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-alpha (EF1alpha) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or gammac overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.
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PMID:Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression. 2043 93


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