**8. Treatment**

Basically, the treatment of Wiskott-Aldrich syndrome depends on supportive care which includes Broad-spectrum antibiotics for bacterial, fungal, or viral infections. Furthermore, platelet supplement, Topical steroids and prevent bleeding, are other treatments. However, a series of controversial treatment are as follows (**Table 3**).

#### **8.1 Intravenous Immunoglobulin therapy**

Intravenous immunoglobulin (IVIG) therapy in WAS and XLT patients with significant antibody deficiency has led to efficient results. IVIG should be administered at physiological doses to patients with recurrent infectious complications and low levels of immunoglobulin or abnormal antibody responses [6]. Because of the increasing catabolic rate observed in WAS patients, the dose is higher than other immunodeficiency diseases. Since these people are more likely to bleed, a Subcutaneous injection of the IVIG is recommended [33]. In the presence of autoimmune manifestations, at least intermittently, immunosuppressive therapy may be required.


#### **Table 3.**

*Therapeutic approaches in Wiskott-Aldrich syndrome.*

#### **8.2 Splenectomy**

Splenectomy is used to slow down the process of thrombocytopenia and stop bleeding by increasing the number of circulating platelets. Patients undergoing splenectomy consume antibiotics for life also they are highly vulnerable to septicemia [2]. Splenectomy is not recommended for people who are going to have Hematopoietic cell transplantation (HCT) in the future because it increases the risk of significant infectious complications [6, 7].

#### **8.3 Eltrombopag**

It is an oral thrombopoietin receptor agonist approved for the treatment of ITP which is claimed to probably effective in preventing bleeding in patients with WAS waiting for HCT [34].

#### **8.4 Immunosuppressive treatment**

More often than not, prescribing immunosuppressive drugs (e.g., cyclophosphamide, azathioprine) is necessary for the autoimmune phenomenon [35]. Most of the time, Monoclonal antibody rituximab may be effective in cytopenias due to Autoimmune disorders and it should be noted that the aforementioned antibody partly is harmless for patients already receiving therapy with IVIG [2].

#### **8.5 Hematopoietic cell transplantation (HCT)**

In a way, it can be said HCT is a unique treatment for patients with human leukocyte antigen (HLA)-matched family or unrelated donors (URDs) or relatively matched cord-blood donors [2].

Newly, according to haploidentical donors, novel graft manipulation approaches that alleviate the risk of graft versus host disease (GVHD) and elevate the possibility of successful engraftment, as well as immune system reconstruction, have yielded promising results in patients with WAS [36]. Reports indicate that The older you are at the time of transplantation, the lower your chances of survival, with different studies indicating different thresholds (e.g., age < 2 or < 5 years) [37, 38].

**189**

*Wiskott-Aldrich Syndrome*

tions [43].

**8.6 Gene therapy**

MN1 genes [44, 45].

*DOI: http://dx.doi.org/10.5772/intechopen.97220*

Despite the high chance of survival after transplantation for WASP patients, these patients are still at risk for post-HCT complications, among which autoimmunity is a prominent problem. It has been reported that up to 55% of transplanted WAS subjects develop autoimmune manifestations, mostly involving antibodymediated cytopenias [39–42]. Although the risk of death in HCT is inevitable, according to a pervasive theory, patients with the severe phenotype (clinical score 3 and above) should be transplanted. For WAS patients with milder clinical manifestations, there is no unanimous opinion, and the decision to continue HCT is made on a case-by-case basis. The results of the decision-making process were the result of a retrospective study of the outcome of HCT in a group of 24 milder patients between 1990 and 2011 who were transplanted at various centers around the world. This study indicated a survival rate of 83% in the absence of long-term complica-

Approximately, HCT from HLA-identical family donors is available to less than 20% of transplanted WAS patients [40, 43]. Although this approach is evolving [36], the increasing complications and mortality of HCT from mismatched donors [40] provide the idea for research into alternative kinds of gene therapy. Gene therapy prepares an enormous of potential advantages over allogeneic HCT, including availability for all patients, reduce transplant rejection risks and prevent GVHD risks, which successively eliminates the necessity to follow special diets and take immunosuppressive drugs. For the primary time in Germany, gene therapy for WAS was accomplished in a clinical trial, during which a gamma-retroviral vector was used to correct CD34+ cells from ten WAS patients. As a result of this investigation, nine of those individuals showed a significant increase in platelet count and rehabilitation of immune responses. But unfortunately, seven patients developed acute leukemia related to vector integration-mediated activation of the LMO2, MDS1, or

A High and unacceptable rate of cancer incidence in gamma-retroviral gene therapy paves the way for the implementation of clinical gene transfer protocols using HIV 1-based constructs [46]. Currently, a series of clinical trials in Europe and the U.S. using these lentiviral vectors have yielded encouraging preliminary results In 2010, when the primary trial was launched, Italian investigators have treated a minimum of 10 patients (F. Ferrua, personal communication, Barcelona, September 2016) with infusions of gene-corrected bone marrow and/or mobilized peripheral blood CD34+ hematopoietic cells. Then, they controlled the possible side effects by prescribing busulfan, fludarabine, and rituximab. The results of the first three patients ≥ 1 year after gene therapy indicated an improvement in platelet count and immune cell function additionally a reduction in severe infections and an improvement in eczema [47, 48]. The results of studies on the effect of gene therapy on defective B cells in patients with WAS indicate that standard distribution of bone marrow and peripheral blood cell subsets, in treated patients, is achievable. most significantly, a serious decrease within the abundance of naive B cells producing reactive antibodies, which are involved in improving the quantity of circulating

The second investigation, conducted in London and Paris, using the identical lentiviral vector and a uniform reparative chemotherapy regimen, 6 out of seven patients treated also demonstrated improvement of immune function and clinical manifestations during 6–42 months of follow-up. Furthermore, during this study, no vector-mediated clonal expansions have occurred [51]. Of note, although in both

antibodies altogether treated patients, was observed [49, 50].

#### *Wiskott-Aldrich Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97220*

Despite the high chance of survival after transplantation for WASP patients, these patients are still at risk for post-HCT complications, among which autoimmunity is a prominent problem. It has been reported that up to 55% of transplanted WAS subjects develop autoimmune manifestations, mostly involving antibodymediated cytopenias [39–42]. Although the risk of death in HCT is inevitable, according to a pervasive theory, patients with the severe phenotype (clinical score 3 and above) should be transplanted. For WAS patients with milder clinical manifestations, there is no unanimous opinion, and the decision to continue HCT is made on a case-by-case basis. The results of the decision-making process were the result of a retrospective study of the outcome of HCT in a group of 24 milder patients between 1990 and 2011 who were transplanted at various centers around the world. This study indicated a survival rate of 83% in the absence of long-term complications [43].

## **8.6 Gene therapy**

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

Splenectomy is used to slow down the process of thrombocytopenia and stop bleeding by increasing the number of circulating platelets. Patients undergoing splenectomy consume antibiotics for life also they are highly vulnerable to septicemia [2]. Splenectomy is not recommended for people who are going to have Hematopoietic cell transplantation (HCT) in the future because it increases the risk

It is an oral thrombopoietin receptor agonist approved for the treatment of ITP which is claimed to probably effective in preventing bleeding in patients with WAS

More often than not, prescribing immunosuppressive drugs (e.g., cyclophosphamide, azathioprine) is necessary for the autoimmune phenomenon [35]. Most of the time, Monoclonal antibody rituximab may be effective in cytopenias due to Autoimmune disorders and it should be noted that the aforementioned antibody

In a way, it can be said HCT is a unique treatment for patients with human leukocyte antigen (HLA)-matched family or unrelated donors (URDs) or relatively

that alleviate the risk of graft versus host disease (GVHD) and elevate the possibility of successful engraftment, as well as immune system reconstruction, have yielded promising results in patients with WAS [36]. Reports indicate that The older you are at the time of transplantation, the lower your chances of survival, with different studies indicating different thresholds (e.g., age < 2 or < 5 years) [37, 38].

Newly, according to haploidentical donors, novel graft manipulation approaches

partly is harmless for patients already receiving therapy with IVIG [2].

**188**

**8.2 Splenectomy**

Splenectomy Eltrombopag

Gene therapy

**Table 3.**

Conventional treatments Broad-spectrum antibiotics platelet supplement Topical steroids Potential treatments

Intravenous immunoglobulin (IVIG)

Hematopoietic cell transplantation (HCT)

*Therapeutic approaches in Wiskott-Aldrich syndrome.*

Immunosuppressive treatment

**8.3 Eltrombopag**

waiting for HCT [34].

**8.4 Immunosuppressive treatment**

matched cord-blood donors [2].

**8.5 Hematopoietic cell transplantation (HCT)**

of significant infectious complications [6, 7].

Approximately, HCT from HLA-identical family donors is available to less than 20% of transplanted WAS patients [40, 43]. Although this approach is evolving [36], the increasing complications and mortality of HCT from mismatched donors [40] provide the idea for research into alternative kinds of gene therapy. Gene therapy prepares an enormous of potential advantages over allogeneic HCT, including availability for all patients, reduce transplant rejection risks and prevent GVHD risks, which successively eliminates the necessity to follow special diets and take immunosuppressive drugs. For the primary time in Germany, gene therapy for WAS was accomplished in a clinical trial, during which a gamma-retroviral vector was used to correct CD34+ cells from ten WAS patients. As a result of this investigation, nine of those individuals showed a significant increase in platelet count and rehabilitation of immune responses. But unfortunately, seven patients developed acute leukemia related to vector integration-mediated activation of the LMO2, MDS1, or MN1 genes [44, 45].

A High and unacceptable rate of cancer incidence in gamma-retroviral gene therapy paves the way for the implementation of clinical gene transfer protocols using HIV 1-based constructs [46]. Currently, a series of clinical trials in Europe and the U.S. using these lentiviral vectors have yielded encouraging preliminary results In 2010, when the primary trial was launched, Italian investigators have treated a minimum of 10 patients (F. Ferrua, personal communication, Barcelona, September 2016) with infusions of gene-corrected bone marrow and/or mobilized peripheral blood CD34+ hematopoietic cells. Then, they controlled the possible side effects by prescribing busulfan, fludarabine, and rituximab. The results of the first three patients ≥ 1 year after gene therapy indicated an improvement in platelet count and immune cell function additionally a reduction in severe infections and an improvement in eczema [47, 48]. The results of studies on the effect of gene therapy on defective B cells in patients with WAS indicate that standard distribution of bone marrow and peripheral blood cell subsets, in treated patients, is achievable. most significantly, a serious decrease within the abundance of naive B cells producing reactive antibodies, which are involved in improving the quantity of circulating antibodies altogether treated patients, was observed [49, 50].

The second investigation, conducted in London and Paris, using the identical lentiviral vector and a uniform reparative chemotherapy regimen, 6 out of seven patients treated also demonstrated improvement of immune function and clinical manifestations during 6–42 months of follow-up. Furthermore, during this study, no vector-mediated clonal expansions have occurred [51]. Of note, although in both trials the duration of bleeding was significantly reduced in number and severity, and also the treated patients not needed blood transfusions and thrombopoietin receptor agonists, platelet counts failed to normal in either trial that it isn't clear. The third trial of WAS gene therapy supported lentiviral vector has recently begun in Boston, USA [52]. At the identical time, other US researchers have developed an alternate lentiviral vector with a stronger WASp expression that's being developed for future clinical applications [53, 54].

In line with current studies, it will be acknowledged that gene modification by lentivirus from autologous hematopoietic ancestors can have significant benefits for patients undergoing treatment and be considered as treatment options for WAS. However, more comprehensive studies are needed to ascertain whether this type of gene therapy could also be a definitive treatment for patients.

### **9. Conclusions**

Despite the rarity of WAS, extensive progress has been made in understanding its pathophysiological foundations, but it is still necessary to establish multifaceted management to assess various aspects of the disease. It is worth noting that health care centers have been pioneers in the diagnosis and management of WAS. Significant advances in allogeneic HCT and its valuable long-term results have made it a viable treatment option for most patients with WAS. For severe manifestations, for example, definitive treatment with HCT is recommended. However, even in a clear clinical situation, HCT may not be available due to the patient's geographical location or socioeconomic status, so supportive care measures should be taken promptly. The same is true of WAS cases with milder clinical manifestations; In fact, more emphasis is placed on accepting the potential risks of treatment in proportion to the severity of the disease manifestations.

Gene therapy is a potential treatment solution for WAS patients with severe and even mild phenotypes. In this regard, the emergence of advances in the use of gene editing technology creates a cautious optimism. However, the financial and geographical problems for patients with limited access to gene therapy options need to be addressed.

#### **Acknowledgements**

This work has been financed by Intechopen publications and I would like to thank Dr. Hridayesh Prakash as well as dear Ms. Marijana Francetic for closed cooperation and sincere support. I thank Dr. David Buchbinder from Children's Hospital of Orange Country and Dr. Hans D. Ochs from the University of Washington for their sincere cooperation and support.

#### **Conflict of interest**

The authors declare no conflict of interest.

### **Thanks**

I am grateful to my family, Dr. Tooba Ghazanfari from Shahed University, Dr. Farideh Talebi from Shahed University, Dr. Mohammad Mahmoudi from Iran

**191**

**Author details**

Saeed Sepehrnia

Department of Immunology, School of Medicine, Shahed University, Tehran, Iran

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: sepehrniasaeed@gmail.com

provided the original work is properly cited.

*Wiskott-Aldrich Syndrome*

**Abbreviations used**

*DOI: http://dx.doi.org/10.5772/intechopen.97220*

HCT Hematopoietic stem Cell

IVIG Intravenous immunoglobulin WAS Wiskott-Aldrich syndrome

ITP Idiopathic thrombocytopenic purpura

WASp Wiskott-Aldrich syndrome protein XLT X-linked thrombocytopenia XLN X-linked neutropenia

University, Dr. Hamed Afkhami from Shahed University, Dr. Roghaye Afifirad from Tehran University as well as MSc. Sayed Esmaeil Ahmadi from Iran University and

also Mr. Mohammad Hosein Siahkary from Qom Islamic Azad University.

*Wiskott-Aldrich Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97220*

University, Dr. Hamed Afkhami from Shahed University, Dr. Roghaye Afifirad from Tehran University as well as MSc. Sayed Esmaeil Ahmadi from Iran University and also Mr. Mohammad Hosein Siahkary from Qom Islamic Azad University.
