Outcome in patients with Wiskott–Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan

Kobayashi, Ryōji; Ariga, Tadashi; Nonoyama, Shigeaki; Kanegane, Hirokazu; Tsuchiya, Shigeru; Morio, Tomohiro; Yabe, Hiromasa; Nagatoshi, Yoshihisa; Kawa, Keisei; Tabuchi, Ken; Tsuchida, Masahiro; Miyawaki, Toshio; Kato, Shingo

doi:10.1111/j.1365-2141.2006.06297.x

Cited by 87 publications

(70 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[83][84][85][86] On the other hand, transplantation using the bone marrow of a mismatched related donor results in a decreased survival rate. [83][84][85][86] In addition, this type of transplantation is associated with an elevated risk of developing life-threatening EBV ϩ lymphoproliferative syndrome, infections, autoimmunity, and graft-versushost disease. 84 When a suitable related donor is not available, bone marrow or cord blood transplantation from a matched unrelated donor is a valid therapeutic option, leading to a 71% to 81% survival rate.…”

Section: Current Therapeutic Approaches and Perspectives For Gene Thementioning

confidence: 99%

“…23,84,85 A better outcome for matched unrelated donor and mismatched related donor HSCT in patients younger than 5 and 2 years of age, respectively, has been reported, suggesting that transplantations should be performed early in life. 79,84,85 Successful HSCT with establishment of full chimerism leads to restoration of immune and hemostatic functions. In patients with stable mixed chimerism in both myeloid and lymphoid compartments, clinical conditions usually improve.…”

Section: Current Therapeutic Approaches and Perspectives For Gene Thementioning

confidence: 99%

“…84 When a suitable related donor is not available, bone marrow or cord blood transplantation from a matched unrelated donor is a valid therapeutic option, leading to a 71% to 81% survival rate. 23,84,85 A better outcome for matched unrelated donor and mismatched related donor HSCT in patients younger than 5 and 2 years of age, respectively, has been reported, suggesting that transplantations should be performed early in life. 79,84,85 Successful HSCT with establishment of full chimerism leads to restoration of immune and hemostatic functions.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome

Bosticardo

Marangoni

Aiuti

et al. 2009

Blood

213

203

View full text Add to dashboard Cite

IntroductionWiskott-Aldrich syndrome (WAS, OMIM 301000) is a complex and severe X-linked disorder characterized by microthrombocytopenia, eczema, immunodeficiency, and increased risk in developing autoimmunity and lymphomas. WAS affects 1 to 10 of every 1 million male newborns; life expectancy is approximately 15 years for patients lacking WAS protein (WASP) expression. 1,2 The protein encoded by the WAS gene (WASP) is a hematopoietic specific regulator of actin nucleation in response to signals arising at the cell membrane. 3,4 Mutations impairing but not abolishing WASP expression can cause X-linked thrombocytopenia (XLT). This disease can be chronic 5 or intermittent 6 and is considered an attenuated form of WAS because it is characterized by low platelet counts with minimal or no immunodeficiency. Recently, gain-of-function mutations in the WAS gene, giving rise to a constitutively active protein, were found to cause a distinct pathology, X-linked neutropenia. X-linked neutropenia is characterized by low neutrophil counts and predisposition to myelodysplasia in the absence of thrombocytopenia and T-cell immunodeficiency. 7,8 The wide spectrum of clinical manifestations highlights the complex role of WASP in various cellular mechanisms. Clinical manifestations in WAS MicrothrombocytopeniaAmong clinical manifestations, hemorrhages are frequent (Ͼ 80% incidence) in WAS and XLT patients and range from nonlife-threatening (epistaxis, petechiae, purpura, oral bleeding) to severe manifestations, such as intestinal and intracranial bleeding. 9 Death of WAS patients is caused, in 21% of the cases, by hemorrhages. 9,10 Bleeding is the result of severe thrombocytopenia with reduced platelet size, which is the most common finding in WAS and XLT patients (100% incidence). Thrombocytopenia occurs irrespectively of the severity of the mutation and is possibly caused by instability of mutated WASP in platelets. 11 Despite intensive research, the mechanisms underlying WASPrelated thrombocytopenia and hemorrhages are not completely understood. Megakaryocyte numbers have been reported to be normal in the majority of WAS patients, 12-14 whereas proplatelet formation depending on actin polymerization and formation of branching structures is conserved when tested in in vitro and ex vivo cultures. 12 Peripheral destruction of platelets in the spleen is thought to play an important role in thrombocytopenia because a substantial correction of the platelet count and size after splenectomy has been reported. 15 The accelerated destruction could be caused by an intrinsic defect of WASP-deficient platelets, showing an increased surface exposure of phosphatidylserine, or could be mediated by autoimmune reaction because of the presence of antiplatelet antibodies reported in patients and in the murine knockout model, 13 although the latter hypothesis is still a matter of controversy in the field. Finally, defects in filopodia and podosomes could play an additional role in migration of megakaryocytes from the endosteal to the perivascular n...

show abstract

Section: Current Therapeutic Approaches and Perspectives For Gene Thementioning

confidence: 99%

Section: Current Therapeutic Approaches and Perspectives For Gene Thementioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome

Bosticardo

Marangoni

Aiuti

et al. 2009

Blood

213

203

View full text Add to dashboard Cite

show abstract

“…7,16 This broad range of manifestations is explained by WASp function, which is tightly associated with the actin cytoskeleton formation, especially in actin polymerization. 3,11,17,18 A successful therapy for WAS can be achieved by allogenic bone marrow (BM) stem cell transplantation 19,20 or unrelated umbilical cord blood transplantation when a compatible donor is not available, 21 but the risk of graft vs host disease and rejection cannot be excluded in any case. [19][20][21] To overcome these limitations, gene therapy using autologous haematopoietic stem cells (HSCs) is a real alternative for treating WAS patients.…”

Section: Introductionmentioning

confidence: 99%

Improved lentiviral vectors for Wiskott–Aldrich syndrome gene therapy mimic endogenous expression profiles throughout haematopoiesis

et al. 2008

View full text Add to dashboard Cite

Wiskott-Aldrich syndrome (WAS) gene therapy requires highly efficient and well-controlled vectors. Here we studied the performance of a lentiviral vector (LV) harbouring a 500-bp fragment of the WAS proximal promoter (WW), which we previously characterized as haematopoietic-specific and capable of restoring WAS phenotype in patients' T cells. We used an LV (WE) expressing eGFP to evaluate whether this promoter was following the expression pattern of endogenous WASp. Transgene expression was analysed in WE-transduced hCD34 + population and its progeny after in vitro and in vivo differentiation in the Rag 2 À/À , gc À/À humanized mouse. We revealed very poor expression from the WE internal promoter in macrophages and erythroid cells. Therefore, we designed a novel LV including a fragment of the alternative WAS promoter in WE vector (AWE). This new vector sustained high transgene levels along the whole lymphoid lineage in vivo. Most importantly, the performance of AWE vector was highly superior to WE vector since AWE clearly improved transgene levels in in vitro and in vivo hCD34 + -derived macrophages, erythroid cells, megakaryocytes and B cells while supporting a high expression in human T cells. This emphasizes that it is a suitable LV backbone for gene therapy of haematopoietic diseases such as WAS. Gene Therapy (2008) 15, 930-941;

show abstract

“…A study performed in Japan on 57 WAS patients treated with HSCT showed that 5 year-old patients suffering from classic WAS, at the time of transplantation had increased susceptibility to infection and hemorrhage diathesis had shown already poor prognosis. Therefore, timely diagnosis and starting treatment of WAS seems to be very important (9). Interestingly, in our study all the symptoms and infections vanished after treatment with monthly IVIG and prophylactic antibiotics, and treatment with HSCT was not needed.…”

Section: Discussionmentioning

confidence: 71%

Evaluation of Classic Wiskott Aldrich Syndrome with Mild Symptoms in Two Cousins: A Case Report

Shirkani

Farrokhi

2017

Iran J Pediatr

View full text Add to dashboard Cite

Introduction: Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity. Commonly, classic WAS is presented with severe clinical symptoms. Case Presentation: We report a new phenotype of classic Wiskott-Aldrich syndrome with mild symptoms in two cousins who were 7 years old. They had not severe infections or hemorrhage, in spite of having genetic mutation in WAS gene. The symptoms and infections of the patients responded to treatment with IVIG and antibiotics. Conclusions: This report is presenting a novel clinical phenotype of classic WAS with milder symptoms.

show abstract

Outcome in patients with Wiskott–Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan

Cited by 87 publications

References 22 publications

Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome

Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome

Improved lentiviral vectors for Wiskott–Aldrich syndrome gene therapy mimic endogenous expression profiles throughout haematopoiesis

Evaluation of Classic Wiskott Aldrich Syndrome with Mild Symptoms in Two Cousins: A Case Report

Contact Info

Product

Resources

About