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Review Article
How I Treat Primary Immune Deficiencies with Hematopoietic Stem Cell Transplantation
Clin Pediatr Hematol Oncol 2022;29:35-43.
Published online October 31, 2022
© 2022 Korean Society of Pediatric Hematology-Oncology

Hoon Kook1,2, Boram Kim2 ,and Hee Jo Baek1,2

1Department of Pediatrics, Chonnam National University Medical School, Gwangju, 2Department of Pediatrics, Chonnam National University Hwasun Hospital, Hwasun, Korea
Correspondence to: Hoon Kook
Department of Pediatrics, Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun, Chonnam 58128, Korea
Tel: +82-61-379-7693
Fax: +82-61-379-7697
E-mail: hoonkook@chonnam.ac.kr
ORCID ID: orcid.org/0000-0002-9135-5821
Received September 13, 2022; Revised October 23, 2022; Accepted October 25, 2022.
Abstract
Primary immune deficiencies (PID), or more recently, inborn errors of immunity (IEI), resulting from genetic defects of the immune system may present with increased susceptibility to infections, persistent inflammation, and autoimmunity. With recent introduction of next generation sequencing, the number of IEIs increases rapidly, reaching to 484 in 2022. Hematopoietic stem cell transplantation (HSCT) has been used over decades as a mainstay of specific treatment modality, while gene therapy and pharmacologic approach have been attempted with promising results in some PID in recent years. The survival following allogeneic HSCT for PID is now generally >80%. The indication and timing of transplant must be individualized not only on the basis of the specific PID but also on the characteristics of the individual patient. For the successful transplant outcome, the choice of donor and the optimal pretransplant conditioning regimen is important. This article will discuss current status and recommendations from specialists in HSCT for some representative PID, including severe combined immunodeficiency (SCID), CD40 ligand or CD40 deficiency, Wiskott-Aldrich syndrome, hemophagocytic lymphohistiocytosis, and chronic granulomatous disease, along with our personal experience of PID treatment in Korea.
Keywords: Primary immunodeficiency, Inborn errors of immunity, Next generation sequencing, Hematopoietic stem cell transplantation
Introduction

1) Definition and categories

Primary immune deficiencies (PID) are characterized by increased susceptibility to infections, due to genetic defects involving development and/or function of the immune system. After the first description of a boy suffering from recurrent pneumococcal infections, who lacked serum gamma globulines by Bruton (1952) [1], the first classification of PID including several distinct disorders was proposed in 1968 [2]. Manifestations of PID can range from life-threatening infections in infancy, to susceptibility to common infections, persistent inflam-mation, and autoimmunity in adulthood. As much as 1% of population may have a PID, which is more than previously predicted [3]. Over the several decades, it has been realized that autoimmunity, autoinflammation, allergy, and malignancy can be common, and predominant in some, clinical manifestations associated with monogenic defects of immunity. To encompass this broad range of phenotypes associated with these disorders, the term “inborn errors of immunity” (IEI) has been proposed [4]. Now many cases with autoimmune cytopenias, inflam-matory bowel diseases, or primary immune regulation disorders are designated as a form of IEIs.

Advances in molecular genetics and cellular immunology, especially the introduction of next generation sequencing (NGS), have permitted a precise definition of various IEIs and identification of sky-rocketing number of IEIs in recent years [5]. The expert committee of the International Union of Immunological Society (IUIS) on IEI has proposed genotypic classification of all IEIs every other year since 2013 to facilitate research on as well as diagnosis of IEIs worldwide. For 2019 phenotypic classification the key clinical and laboratory features of 430 IEIs were reported within 10 broad categories of IEIs [6,7]. The IUIS Expert Committee undated the classification in 2022 which includes a total of 484 IEIs. Since the previous update features of 55 novel monogenic gene defects and 1 phenocopy due to autoantibodies were added [8]. IEIs are currently categorized into 10 groups: 1) combined immunodeficiencies; 2) combined immuno-deficiencies with syndromic features; 3) predominantly antibody deficiencies; 4) diseases of immune dysregulation; 5) congenital defects of phagocytes; 6) defects in intrinsic and innate immunity; 7) autoinflammatory diseases; 8) complement deficiencies; 9) bone marrow failure; and 10) phenocopies of inborn errors of immunity [7,8].

In Korea, only a few studies have been conducted to evaluate the prevalence of PID. A retrospective analysis of PID from 2001 to 2005 identified 152 cases of various diseases [9]. More recently, a total of 398 cases were collected through the literature review (2001-2018) and big data analysis of National Health Insurance System, Korea on year 2017 [10]. The small number of PID cases in Korea reported reflects underestimation of cases due to difficult genetic diagnosis of diverse phenotypes in earlier days. Newborn screening for severe combined immunodeficiency (SCID), which has just been introduced in the United States, and several European countries would be a hope for early diagnosis and treatment for PID [11,12].

2) Treatment modalities of PID/IEIs

In parallel with the advances in cellular and molecular studies on IEIs, treatment paradigm has been shifted from supportive care, mostly focusing on prevention and treatment of infection and inflammation to precision medicine. The first allogeneic hematopoietic stem cell transplantation (HSCT), successfully performed in a baby with X-lined SCID has paved the way for the application of HSCT to a large number of otherwise fatal immunodeficiency diseases as well as a variety of hematologic and malignant diseases [5,13,14]. Moreover, targeted therapeutic approaches based on replacement of the missing product were attempted for the first time in patients with adenosine deaminase (ADA)-SCID, and approved later by FDA [15]. Other examples of pharmacological approaches among others are: use of IL1 antagonist in autoinflammatory diseases, use of CTLA4-Ig in the treatment of CTLA4- and LRBA- deficiencies, PI3Kd inhibitors in APDS, complement inhibitor in CD55 deficiency, and JAK inhibitors in gain of function mutations in STAT-1/3 [5]. However, details are beyond the scope of this review article.

The correction of the gene defects could provide definitive cure to patients with IEIs [16]. First gene therapy was attempted for ADA-SCID patients, initially using gene modified autologous T cells in 1992 and later combined with hematopoietic stem cell precursors (HSPCs) [17]. Initial clinical success in patients with ADA-SCID, X-linked recessive (XR)-SCID and Wiskott-Aldrich syndrome (WAS) based on first generation g-retroviral vectors encountered a significant obstacle of development of T-cell acute lymphoblastic leukemia due to insertional mutagenesis [18,19]. This led investigators to develop safer vector delivery systems. Now, self-inactivating lentivirus (SIN-LV) vectors are considered the most efficient and safest gene delivery vectors for both T cells and HSPCs [5,16]. Most recently, gene editing using CRISPER/ Cas9 nuclease system might be fascinating because it preserves spatiotemporal regulated gene expression [20]. Preclinical trials are underway for several IEIs, including XR-SCID, hyper-IgM syndrome, and IPEX.

Regarding to the treatment modalities for patients with PID, a survey of physician-reported data was performed through the Jeffrey Modell Foundation global network. For the year 2021 the number of patients with severe PID to receive specific therapies other than immunoglobulins was 7,406 worldwide. Most of the patients were treated by HSCT (n=7,032, 94.9%), followed by gene therapy (n=248, 3.3%), and pegylated-ADA (n=126, 1.7%) [21]. Thus, although gene therapy seems to be very promising in growing numbers of IEIs, HSCT remains the most important treatment modality in current practice worldwide, as the affordability of gene therapy remains a major financial and ethical challenge [5].

3) Hematopoietic stem cell transplantation

The survival following allogeneic HSCT for PID is now generally >80% with gradual improvement over half century in transplantation technology, including high- resolution HLA typing, increased use of alternative donors, adoption of less toxic conditioning regimens and pharmacokinetic monitoring, development of more effective T-cell depletion methods, and better supportive care. In addition, early identification of infants with SCIDs by genetic diagnosis with NGS prior to infectious complications contributed to a better survival [22-24]. However, the diverse spectrum of PID with clinical and immunologic phenotypes caused by more than 450 monogenic gene defects makes it difficult to define a universal transplant regimen. As such, integration of immunologic and genetic knowledge into transplantation field is necessary for the development of innovative and improving transplant protocols.

This article will discuss current status and recommendations from specialists in HSCT for PID. Although PID stemming from defects in the hematopoietic compartment are largely cured by HSCT, immunologic diseases due to thymic stromal or other extra-hematopoietic defects are not likely to be corrected by HSCT. Table 1 summarizes classical indications for HSCT in PID [24,25]. However, the list of indications needs to be updated in accordance to the improvement of transplant technology and addition of new types of PID. Moreover, the indication and timing of transplant must be individualized not only on the basis of the specific PID but also on the characteristics of the individual patient.

Table 1 . Classical indications for HSCT in PID.

HSCT curative
SCID (severe combined immunodeficiency)
CID (combine immunodeficiency)*
CGD (chronic granulomatous disease)
DOCK8 (dedicator of cytokinesis) deficiency
DOCK2 deficiency
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
WAS (Wiskott-Aldrich syndrome)
WIP (WASP interacting protein) deficiency
ARPC1B (actin related protein 2/3 complex subunit)
CD40 ligand deficiency
XLP1,2 (X-linked lymphoproliferative disease)
APDS (activated PI3K delta syndrome)
MHC (major histocompatibility complex) class II deficiency
AD (autosomal dominant) hyper IgE syndrome
CTLA4 (cytotoxic T-lymphocyte-associated protein) hyploinsufficiency
LRBA (lipopolysaccharide [LPS]-responsive and Beige-like anchor protein) deficiency
Familial HLH (hemophagocytic lymphohemophagocytosis) types 1-5
GATA2 (GATA binding protein) deficiency
RAB27A (member RAS oncology family) deficiency
LAD1 (leukocyte adhesion deficiency)
Reticular dysgenesis
HSCT partially curative
Cartilage hair hypoplasia
PGM3 (phosphoacetylglucosamine mutase) deficiency
STAT1 (signal transducer and activator of transcription) - GOF (gain of function)
STAT3 - GOF
Severe congenital neutropenia
ADA2 (adenosine deaminase) deficiency
C1q deficiency
CD25 deficiency
IL-10 deficiency
IL-10 receptor deficiency
DNA double-strand break repair disorders
HSCT controversial
CVID (common variable immunodeficiency)
Agammaglobulinemia
Complement deficiencies (other than C1q deficiency)
DiGeorge syndrome
NEMO (nuclear factor-kappa B [NF-kB] essential modulator) deficiency
IKBA (inhibitor of NF-kB alpha) deficiency
*Depending on the clinical and immunological phenotypes.
HSCT, hematopoietic stem cell transplantation; PID, primary immune deficiencies.


The use of alternative donors and new graft manipulation techniques has also dramatically improved access to allogeneic HSCT. The gold standard for HSCT has been using matched related donors, but they should be evaluated for the possibility of recurrence of the disease in the family. Although the outcome of HSCT from matched unrelated donors are equivalent to those from matched siblings, only a minor proportion of the patients in need may benefit from those donors. Recently, haploidentical transplants with ex vivo T-cell receptor (TCR) ab/CD19-depleted grafts or T replete marrow with post- transplant cyclophosphamide (PT-CY) approach have demonstrated promising results in patients with PID without development of life-threatening graft-versus-host diseases (GvHD) [26,27]. Depletion of subset of naïve T lymphocytes bearing CD45RA marker might preserve anti- viral activity which is conferred by CD45RO cells [28].

Pre-transplant conditioning is essential component of successful allogeneic HSCT for both malignant and benign hematologic diseases. However, HSCT for PID differs from that for other hematological malignancies in that the goal is not to eradicate certain immune cells but to achieve immune reconstitution in general. Although a small portion of SCID cases may not need conditioning before stem cell infusion, most of PID or IEI patients need a conditioning regimen to achieve a high donor chimerism, which is known to be associated with better outcomes and improved quality of life (QOL) [29]. Myeloablative conditioning using busulfan and cyclophosphamide was the norm in earlier days, but modified conditioning regimens significantly contributed to improved HSCT outcome by reducing short- and long-term transplant-related mortality and morbidity [14,24]. The substitution of cyclophosphamide with fludarabine, and the development of pharmacokinetics-based busulfan dosing as well as treosulfan-based conditioning have resulted in decreased toxicity and stable engraftment [30-32]. The Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) and the European Society for Immune Deficiencies (ESID) recently published guidelines for HSCT for IEI. They recommend six protocols (A-F) as conditioning regimens based on reported data, center experiences and expert opinions rather than prospective studies (Fig. 1) [14]. Protocol A and protocol B are myeloablatvie conditioning regimens recommended for patients without severe preexisting organ damage and non-SCID diseases where a complete donor chimerism is desired for optimal disease correction. Protocols C and D are reduced intensity conditioning (RIC) regimens for patients with preexisting organ damage. Mixed donor chimerism is more likely to occur compared to Protocols A and B. The details of dosing schedules are provided in the article [14]. The choice of myeloablative versus reduced intensity conditioning, and the implication of mixed donor chimerism with acceptable level of mixed chimerism after HSCT will be discussed under specific representative disease categories.

Figure 1. Conditioning regimens for PID recommended by EBMT/ESID inborn errors working party [14]. Protocol A and B: These are recommended for patients without severe preexisting organ damage and non-SCID diseases where a complete donor chimerism is desired for optimal disease correction. Protocols C and D: These are recommended for patients with preexisting organ damage and/or diseases where engraftment has been shown to reliably occur with reduced intensity conditioning. Mixed donor chimerism is more likely to occur compared to protocols A and B. Protocol E: This may be best suited for patients with preexisting organ damage and/or diseases where full myeloid engraftment is not absolutely required. Higher degrees of chimerism can be achieved when using PBSC. DLI may be required in case of mixed chimerism. Protocol F: To avoid organ toxicity this regimen is only recommended for patients with DNA repair/radio-sensitivity disorders (except Artemis deficiency) in which alkylating agents are used in low dose. PID, primary immune deficiencies; EBMT, European Society for Blood and Marrow Transplantation; ESID, European Society for Immune Deficiencies; SCID, severe combined immunodeficiency; PBSC, peripheral blood stem cell; DLI, donor lymphocyte infusion.

Therapeutic drug monitoring for busulfan to optimize exposure is mandatory for Protocols A and C. Because of its favorable toxicity profile, treosulfan was used instead of busulfan, showing similar survival and outcome, but the predictability to reach full donor chimerism is less in the case of treosulfan [25,31]. Fludarabine is a primarily lymphodepleting agent, commonly used in combination with either busulfan or treosulfan instead of cy-clophosphamide. Fludarabine is incorporated in every pro-tocol from A to F. Thiotepa is often used to add myeloablative activity, and has the potential to cross the blood- brain barrier which may be beneficial in diseases with central nervous system (CNS) involvement, such as hemo-phagocytic lymphohistiocytosis (HLH) [33]. Serotherapy consisting of antithymocyte globuline (ATG)/antilymphocyte globulin (ALG) and alemtuzumab is an essential component in most conditioning regimens. Serotherapy is used to facilitate engraftment and to prevent GvHD, especially in unrelated or mismatched family donor settings. Thus, the choice of the optimal conditioning regimen should be considered for each patient based on the phenotype or genotype of IEI, donor type and co-morbidity of the patient.

Now we review current status of HSCT outcomes for several representative PID, along with our personal experience of PID treatment in Korea.

Severe Combined Immunodeficiency (SCID)

SCID is a group of most severe form of immuno-deficiency affecting both cellular and humoral immunity. Affected patients suffer from severe, recurrent, and opportunistic infections from early after birth, and usually die within a year, without definitive treatment. Nineteen different genetic defects are known to be responsible for SCID according to current classification [8]. They are cate-gorized by the molecular pathways affected and immu-nologic phenotypes: SCID T-B+NK+/-, SCID T-B-NK+/- [7]. For SCID T-B+NK-, X-linked SCID with impaired gC signaling and autosomal recessive (AR)-SCID with JAK3 deficiency are indistinguishable in clinical and immuno-phenotypic findings, as JAK3 is coupled with the common g chain of interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors and mediates their downstream signaling.

HSCT has been used as a curative therapy, resulting in 10-yr overall survival after HSCT of 70-80% [24,34]. The later age of HSCT (after 3.5-4 months) or active infection at HSCT is recognized as a risk factor for poor survival after HSCT [29,34]. Choice of conditioning regimen will be mainly based on donor type and SCID phenotype/genotype. In some cases, such as X-SCID or ADA deficiency, conditioning is not required to attain T cell reconstitution, but better functional B and NK cell recovery is achieved with the use of conditioning [14,29,35]. Thus, EBMT/ESID recommended RIC of either Protocol C or Protocol D for all SCID patients irrespective of donor type, but they allowed no conditioning for select cases with T-B+NK-, such as JAK3 or IL2R deficiency or cases of ADA deficiency when matched donor is used [14]. The authors reported the first case of molecularly diagnosed X-SCID in Korea, successfully rescued by CD34+ selected peripheral blood HSCT from haploiden-tical father [36].

CD40 Ligand Deficiency (CD154) or CD40 Deficiency

X-linked hyper-IgM syndrome (XHIGM) is a rare combined immunodeficiency disease (CID), generally less profound than SCID, having recurrent infections associated with low or absent levels of IgG and increased levels of IgM. Binding of CD40 ligand (CD40L, CD154) to its receptor CD40 on B cells is critical for immunoglobulin isotype switching and an effective secondary antibody response. Also its binding to CD40 in dendritic cells and macrophages is engaged in their maturation, activation, and cytokine secretion leading to an effective T-cell response [37]. Patients with defective CD40 signaling, either by CD40L deficiency (XHIGM) or by CD40 deficiency (autosomal recessive in inheritance) are characterized by opportunistic infections, especially Pneumocystis and Cryptosporidium, biliary and liver diseases and chronic or intermittent neutropenia. Long-term outcome of 176 patients with CD40L deficiency was reported. Among them, 85% of 67 patients who received HSCT were surviving, with better outcome with myeloablative condi-tioning than RIC regimen. Liver disease, especially sclerosing cholangitis secondary to Cryptosporidium infection at the time of transplantation was associated with a negative risk factor for survival [37,38]. Because CID patients have impaired, but residual T cell immunity, myeloablative conditioning of protocol A or B is usually preferred. However, patients with older age or preexisting infectious and non-infectious comorbidities may benefit from protocol C or D [14,24]. The first case with molecular diagnosis in Korea who also suffered from Cryptosporidium was reported by the authors [39].

Wiskott-Aldrich Syndrome (WAS)

WAS, one of the examples of CID with associated or syndromic features, is an X-linked recessive disease cause by WAS gene mutation. It is characterized by microthrombocytopenia, eczema, recurrent bacterial and viral infections, bloody diarrhea, lymphoma, and autoimmune diseases. Based on the WASP protein expression, the clinical features manifest a spectrum ranging from X-lined thrombocytopenia to classic WAS with autoimmune complications [8,40]. HSCT has been a definitive therapy for WAS with 5-yr OS of 80-90% in recent studies [29,41]. Age greater than 5 years at HSCT, and the use of mismatched family donors were associated with a poorer outcome. It is noteworthy that mixed chimerism with low myeloid engraftment is associated with poor OS, incomplete immune reconstitution, autoimmunity, and a high risk of thrombocytopenia after HSCT [29,41]. As high intensity conditioning regimens result in reliable donor chimerism, myeloablative conditioning of protocol A or B is usually preferred [14,24]. We reported the first Korean case of HSCT for WAS in 1997 [42].

Hemophagocytic Lymphohistiocytosis (HLH) and Epstein-Barr Virus (EBV) Susceptibility

Familial hemophagocytic lymphohistiocytisis (FHL) syndromes are one of the subgroups of diseases of immune dysregulation. Seven diseases are included in the category: Perforin deficiency (FHL2); UNC13D/Munc13-4 deficiency (FHL3); Syntaxin 11 deficiency (FHL4); STXBP2/ Munc18-2 deficiency (FHL5); FAAP24 deficiency; SLC7A7 deficiency; and RHOG deficiency [8]. HLH is a syndrome of life-threatening systemic hyperinflammation, characterized by unremitting fever, cytopenia, hepatospleno-megaly, coagulopathy, and organ failure, including the liver, CNS and/or others [43]. HSCT is considered to be the only curative therapy for genetic HLH disorders after achieving disease remission following immuno- and myelosuppressive drugs, with the 5-year OS of 60-80% after HSCT [44]. Earlier studies using myeloablative conditioning showed poor outcome after HSCT because of pre-existing multiorgan toxicity and infections before HSCT, and incidence of hepatic venoocclusive disease. The use of RIC containing fludarabine, melphalan, and alemtuzumab or thiotepa, and better HLH control prior to conditioning were associated with better outcome [29,44]. The use of RIC is further supported by the fact that a donor chimerism >20-30% was protective against late reactivation. Thus, complete chimerism was not necessary to suppress HLH [45].

Two forms of X-linked proliferative (XLP) disease are known, showing susceptibility to EBV and lymphoproliferative conditions under the category of disease of immune dysregulation [8]. SAP deficiency, also known as XLP1, is due to mutation of the SH2D1A gene. Resultant deficiency of SLAM-associated protein (SAP) is associated with defective cytotoxic response of T and NK cells. Clinical phenotype of XLP1 is characterized by fulminant infectious mononucleosis, HLH and lymphoma triggered by EBV infection. Aplastic anemia and dysgammaglobulinemia are also found [24]. HSCT using either MAC or RIC has been reported with comparable outcomes in XLP1 (70-80%), but prior HLH was the major risk factor for poor outcome [46,47].

XLP type 2 (XLP2) is due to mutations of the X-linked inhibitor of apoptosis (XIAP) gene, which regulates survival and inflammatory responses. XIAP deficient patients are at high risk for HLH, but not for EBV-related lymphoma. Crohn-like bowel disease as an inflammatory manifestation is frequently observed. In addition, severe infectious mononucleosis, splenomegaly, recurrent infections are often found [48]. The outcome of HSCT for XIAP deficiency has been worse than that of other primary HLH as they are particularly sensitive to alkylating agents, and vulnerable to more severe GvHD [49]. How-ever, the use of RIC and HSCT in remission of HLH resulted in better survival >80% in a recent study, but the associated colitis may take quite a long time to resolve after HSCT [50]. For those patients with HLH and other EBV susceptibility diseases, conditioning regimens A to D are recommended by EBMT/ESID, but serotherapy is advised to be included as a part of conditioning to control disease if not in complete remission [14].

Chronic Granulomatous Disease (CGD)

CGDs are disorders of phagocytic function due to defects of respiratory burst. X-linked and autosomal recessive forms are caused by mutations of the genes for respective subunits of NADPH complex. The main clinical features of CGD include recurrent bacterial and fungal infections from catalase-positive organisms, and high rate of inflammatory complications, such as inflamma-tory bowel disease, and granuloma formation in the liver, lungs and skin [24]. A recent study from EBMT/IEWP reported excellent overall and event-free survival on 712 children and adult patients with CGD [51]. Older age at transplantation, transplant from other than matched siblings, and cord blood transplantation have been associated with poor survival [29,51]. The use of alkylator- based RIC and treosulfan-based RIC have resulted in comparable survival, but graft failure is of concern in some patients [52]. Thus, protocol C and D are the preferred regimens by EBMT/ESID, as reduced toxicity conditioning leads to sustained neutrophil production of donor origin in most of the cases. Moreover, stable mixed chimerism (>20% myeloid) is known to be sufficient to protect against serious infections. Some centers may prefer protocol A or B to favor myeloid engraftment, but direct comparison is not available so far. Every effort should be paid before HSCT to best possible control of autoinflammation, such as colitis, or lung disease. Also, serotherapy consisting of either ATG or alemtuzumab is recommended for all CGD patients to control extensive inflammation [14]. Female carrier donors of X-linked CGD may not be ideal as HSCT donors as many female carriers may have inflammatory and autoimmune symptoms, not related to the degree of lyonization [53].

Conclusion

With advances in molecular genetics and cellular immunology, the definition and identification of specific PID or IEI, now almost reaching to 500 defects, became possible. HSCT has been used as a mainstay of specific treatment for many otherwise lethal PIDs. Recent progresses in HLA typing, expansion of donor availability, choice of optimal conditioning regimen, better supportive care and early diagnosis through newborn screening all have contributed to long-term outcome >80% in recent years. The transplant procedure should be indivi-dualized, and the resultant transplant outcomes including engraftment, chimerism status, transplant-related mortality, GvHD, infection, survival and long-term toxicity should be varied based on the specific PID, timing of HSCT, comorbidities, donor selection, conditioning regimen, and center experiences. Refinement in gene therapy and incorporation of pharmacological approaches will further pave the road to cure for all PID in the future.

Conflict of Interest Statement

The authors have no conflict of interest to declare. 

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October 2023, 30 (2)
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  • Hoon Kook