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

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for the treatment of an otherwise incurable broad spectrum of malignant and non-malignant diseases. Until recently, BMT was used primarily to replace a malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimens were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic cells, including stem cells and their progeny. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells can be mediated by donor lymphocytes in the process of adoptive allogeneic cell therapy following BMT. Thus, eradication of all malignant cells, especially in patients with CML and, to a lesser extent, in patients with other hematologic malignancies can be accomplished despite complete resistance of puch tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-malignancy effects might be used as a tool for eradication of otherwise resistant tumor cells of host origin. We speculated that the therapeutic benefit of BMT may be improved by using safer conditioning for engraftment of donor stem cells induce host-versus-graft unresponsiveness to enable engraftment of donor lymphocytes for subsequent induction of graft-versus-malignancy effects, or even graft-versus-autoimmunity and graft-versus-genetically abnormal cells. In other words, focusing on more selective and smarter rather than stronger modalities. Effective BMT procedures may be accomplished without lethal conditioning of the host, using a new, well-tolerated and user-friendly non-myeloablative regimen, thus eliminating or minimizing immediate and late procedure-related toxicity and mortality. It appears that initial induction of graft tolerance, mediated by engraftment of donor stem cells, leads to durable engraftment of immunocompetent donor lymphocytes, which may be necessary for induction of effective biologic warfare against host-type immunohematopoietic cells. Consequently, stem-cell therapy following induction of transplantation tolerance by selective elimination of alloreactive donor lymphocytes may represent the treatment of choice for a wide range of otherwise incurable diseases, including cancer (hematologic malignancies and certain metastatic solid tumors), genetic disorders (hemoglobinopathies and enzyme deficiency disorders), diseases caused by self-reactive lymphocytes (autoimmune diseases such as multiple sclerosis, rheumatoid arthritis) to mention just a few. Using reduced intensity conditioning, non-myeloablative stem cell transplantation (NST) can be accomplished with no major procedure-related toxicity or mortality. Thus, NST offers the feasibility of safe stem cell transplantation and cell-mediated procedures for a large and constantly growing spectrum of clinical indications for all patients in need without lower or upper age limit. Future strategies currently under investigation include developing new approaches for control of alloreactivity of host-versus-graft and graft-versus host reactivity reactions and developing better approaches for maximizing the capacity of donor lymphocytes to eliminate cancer cells more selectively, while avoiding or minimizing GVHD for safer and more effective treatment of patients in need of BMT.
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PMID:Reduced-intensity conditioning for the treatment of malignant and life-threatening non-malignant disorders. 1538 19

Patients with sickle cell disease (N = 3) and thalassemia (N = 1) with high-risk features received hematopoietic stem cell transplantations (HCT) to induce stable (full or partial) donor engraftment. Patients were 9-30 years of age. Fludarabine, rabbit anti-thymocyte globulin (ATG), and 200 cGy total body irradiation were administered pre-transplant. Patients received bone marrow (N = 3) or peripheral blood stem cells (N = 1) from HLA-identical siblings, followed by mycophenolate mofetil and cyclosporine for post-grafting immunosuppression. Significant lymphopenia, but only moderate neutropenia and thrombocytopenia developed post transplant. No grade IV nonhematological toxicities or acute graft-versus-host disease (GVHD) were observed. At 3 months after transplantation, three of four patients had evidence of donor myeloid chimerism (range, 15-100%). However, after post transplant immunosuppression was discontinued, graft rejection occurred in all but one patient. This patient is now doing well 27 months post transplant with full donor engraftment. One patient died after a second transplant, and another patient experienced a stroke as her graft was being rejected. These results suggest that stable donor engraftment after nonmyeloablative HCT is difficult to achieve among immunocompetent patients with hemoglobinopathies and that new approaches will need to be developed before wider application of this transplantation method for hemoglobinopathies.
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PMID:Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. 1553 1

The only well-established curative therapy for patients with hemoglobinopathies is allogeneic hematopoietic stem cell transplantation (HSCT), which, in the last 20 years, has been mainly performed from an HLA-matched, related donor, using bone marrow as source of hematopoietic progenitors. More recent studies indicate that HSCT from unrelated donors may offer results comparable to those obtained with HLA-identical family donors, provided that stringent criteria of compatibility are employed for selecting the donor. Cord blood transplantation was also suggested to be an equally effective, but safer, procedure than bone marrow transplantation, due to the lower incidence and severity of both acute and chronic graft-versus-host disease. In view of the early, as well as late, morbidity and mortality associated with conventional myeloablative transplantation in patients with hemoglobinopathies, it is not surprising that great interest and relevant expectations for patients with hemoglobinopathies have been raised by the introduction in the clinical practice of reduced-intensity preparative regimens. However, few reports have demonstrated the feasibility of using reduced-intensity preparative regimens for successfully treating these patients and many treatment failures, mainly due to the lack of sustained donor engraftment, have been reported. Despite these limitations, some of the concepts obtained from the use of reduced intensity regimens, such as the substitution of fludarabine for cyclophosphamide, may be important to further improve the outcome of patients with hemoglobinopathies, especially of those with poor prognostic characteristics, given HSCT.
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PMID:Reduced-intensity regimens in allogeneic hematopoietic stem cell transplantation for hemoglobinopathies. 1712 89

The concept of introducing genes into human cells for therapeutic purposes developed nearly 50 years ago as diseases due to defects in specific genes were recognized. Development of recombinant DNA techniques in the 1970s and their application to the study of mouse tumor viruses facilitated the assembly of the first gene transfer vectors. Vectors of several different types have now been developed for specific applications and over the past decade, efficacy has been demonstrated in many animal models. Clinical trials began in 1989 and by 2002 there was unequivocal evidence that children with severe combined immunodeficiency could be cured by gene transfer into primitive hematopoietic cells. Emerging from these successful trials was the realization that proto-oncogene activation by retroviral integration could contribute to leukemia. Much current effort is focused on development of safer vectors. Successful gene therapy applications have also been developed for control of graft-versus-host disease and treatment of various viral infections, leukemias, and lymphomas. The hemophilias seem amenable to gene therapy intervention and informative clinical trials have been conducted. The hemoglobin disorders, an early target for gene therapy, have proved particularly challenging although ongoing research is yielding new information that may ultimately lead to successful clinical trials.
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PMID:Development of gene therapy for blood disorders. 1844 Dec 45

Allogeneic blood or marrow transplantation (BMT) is potentially curative for a variety of life-threatening nonmalignant hematologic diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and hemoglobinopathies. The application of BMT to treat these disorders is limited by the lack of suitable donors and often end-organ damage from the underlying disease. We treated three patients with thrombotic PNH, one of whom also had sickle cell disease, with a nonmyeloablative, HLA-haploidentical BMT with post-transplant CY. Rapid engraftment without GVHD occurred in two of the patients, including the patient with sickle cell disease. Both patients are disease free with full donor chimerism and require no immunosuppressive therapy, with follow-up of 1 and 4 years, respectively. Nonmyeloablative, HLA-haploidentical BMT with post-transplant CY is a promising approach for patients with life-threatening nonmalignant hematologic disease who lack an HLA-matched sibling donor.
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PMID:Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. 1862 13

Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) has become a therapeutic option for an increasing number of patients with otherwise incurable leukemias, solid tumors, immunodeficiencies, hemoglobinopathies and metabolic diseases. For patients requiring an allogeneic transplant, the addition of unrelated cord blood units and partially matched family member donors as alternate stem cell sources has increased the chances that an appropriate donor can be identified. In addition, new approaches to stem cell graft engineering are yielding insights into potential cellular immune therapies, which may decrease the adverse effects of HSCT such as graft-versus-host disease (GVHD) and harness the alloimmune graft-versus-leukemia effect. Novel conditioning regimens, primarily reduced intensity and non-myeloablative regimens, allow patients with significant co-morbidities to undergo transplantation with reduced morbidity and mortality. Combinations of immune-modulatory cytokines and monoclonal antibodies with autologous and allogeneic transplantation are among the advances being explored in contemporary HSCT.
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PMID:Advances in pediatric hematopoietic stem cell transplantation. 1892 94

Many factors, including lower risk of GVHD, rapid availability of 4/6-6/6 matched cord blood (CB) units and incremental gains in the outcomes, have led to an increasing use of CB transplantation (CBT) to treat many patients who lack fully matched adult BM donors. A large electronically searchable worldwide inventory of publicly banked CB units allows for quicker donor identification and selection. In this review, we examine the current status and cumulative experience of related and unrelated donor CBT for the treatment of non-malignant diseases, including hemoglobinopathies, BM failure syndromes, primary immunodeficiency diseases (PIDs) and inherited metabolic disorders (IMDs), and conclude that CBT offers a promising and effective therapy for these diseases. Future strategies to facilitate earlier diagnosis and to decrease transplant-related risks should further improve the short- and long-term outcomes. Every effort should be made to perform transplantation early in the course of disease before extensive damage to various tissues and organs ensues.
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PMID:Umbilical cord blood transplantation for non-malignant diseases. 1980 20

GVHD is a major barrier to broader use of allogenic HSCT for nonmalignancy clinical applications such as the treatment of primary immunodeficiencies and hemoglobinopathies. We show in a murine model of C57BL/6J (H2-k(b)) --> B6D2F1/J (H2-k(b/d)) acute GVHD that when initiated 2 days before transplant, the activation of the adenosine A(2A)R with the selective agonist ATL146e inhibits the weight loss and mortality associated with disease progression. Furthermore, circulating levels of proinflammatory cytokines and chemokines, including IFN-gamma, IL-6, CCL2, KC, and G-CSF, are reduced significantly by 14-day ATL146e treatment. The up-regulation of CD25, CD69, and CD40L expression by donor CD4(+) and CD8(+) T cells is inhibited by A(2A)R activation; fewer CD3(+) T cells are found in the liver, skin, and colon of ATL146e-treated mice as compared with vehicle-treated controls; and associated tissue injury is lessened. The delayed administration of ATL146e, beginning 9 days after HSCT, reverses GVHD-associated body weight loss successfully, and improvement is sustained for the duration of treatment. We conclude that the selective activation of the A(2A)R has therapeutic potential in the prevention and treatment of acute GVHD.
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PMID:Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation. 1988 28

Hematopoietic SCT (HSCT) from HLA-matched donors is sometimes complicated by GVHD or graft rejection, because of mismatched mHA. This study presents data suggesting the involvement of glutathione S-transferase theta-1 (GSTT1), a phase II detoxifying enzyme encoded by GSTT1, in Ab-mediated rejection of HSCT in children with congenital hemoglobinopathies (CHs). Mismatch of GSTT1, which often features a deletion polymorphism variant, can have major consequences in solid organ transplantation outcome. In liver transplantation, it has been shown to lead to de novo hepatitis, whereas in kidney transplantation, chronic allograft rejection has been documented. In this study on 18 children with CH who underwent HSCT, five cases of graft rejection occurred, all in GSTT1-null patients, four of which featured anti-GSTT1 antibodies. The data suggest that when GSTT1-null patients are transplanted with a GSTT1-positive graft, rejection due to an Ab-mediated immune response against GSTT1 displayed on transplanted stem cells may take place. Thus, it seems that detection of anti-GSTT1 antibodies in patients with a GSTT1-null genotype before transplantation may be predictive of graft rejection in the event of a GSTT1-positive donor.
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PMID:Glutathione S-transferase T1-null seems to be associated with graft failure in hematopoietic SCT. 2034 73

Despite the optimization of conventional treatment, both thalassemia and sickle cell disease are still associated with significant morbidity and mortality, especially in developing countries. Allogeneic transplantation of hematopoietic progenitors is the only curative treatment and represents an attractive option for these patients. In view of the low incidence of graft-versus-host disease associated with the procedure, allogeneic cord blood transplantation (CBT) is particularly appealing for patients with non-malignant disorders. Available evidence indicates that related donor CBT is a safe and effective option for patients with hemoglobinopathies, able to offer results at least as good as those reported using bone marrow cells.
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PMID:Cord blood transplantation in patients with hemoglobinopathies. 2038 70


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