Hematopoietic stem cell transplantation for primary immunodeficiency

Genetically determined defects of T-cell development comprise a heterogeneous group of conditions characterized by peripheral T-cell lymphopenia due to impaired intrathymic differentiation of T-cell progenitors. Collectively, these conditions are typically referred to as severe combined immune deficiency (SCID). In some cases (leaky SCID), residual function of the defective gene allows partial T-cell development. The vast majority of SCID disorders are due to genetic defects that affect the T-cell differentiation potential of hematopoietic stem cells, through a variety of mechanisms. However, some forms of SCID reflect impaired development or function of thymic stromal cells. A lack of peripheral T cells leads to increased susceptibility to severe infections since early in life. SCID is inevitably fatal unless immune reconstitution is achieved, most often through hematopoietic cell transplantation. Enzyme replacement therapy, gene therapy, and thymus implantation represent other forms of treatment in selected cases. The availability of newborn screening has greatly facilitated prompt recognition of SCID, which allows statistically significant improvement in survival after hematopoietic cell transplantation.

Genetically-determined defects of T cell development

Notarangelo

2024

Primary antibody deficiencies

Nguyen,

Aquino

2024

Primary antibody deficiencies are characterized by the inability to effectively produce antibodies and may involve defects in B-cell development or maturation. Primary antibody deficiencies can occur at any age, depending on the disease pathology. Certain primary antibody deficiencies affect males and females equally, whereas others affect males more often. Patients typically present with recurrent sinopulmonary and gastrointestinal infections, and some patients can experience an increased risk of opportunistic infections. Multidisciplinary collaboration is important in the management of patients with primary antibody deficiencies because these patients require heightened monitoring for atopic, autoimmune, and malignant comorbidities and complications. The underlying genetic defects associated with many primary antibody deficiencies have been discovered, but, in some diseases, the underlying genetic defect and inheritance are still unknown. The diagnosis of primary antibody deficiencies is often made through the evaluation of immunoglobulin levels, lymphocyte levels, and antibody responses. A definitive diagnosis is obtained through genetic testing, which offers specific management options and may inform future family planning. Treatment varies but generally includes antibiotic prophylaxis, vaccination, and immunoglobulin replacement. Hematopoietic stem cell transplantation is also an option for certain primary antibody deficiencies.

Immunodeficiency: Gene therapy for primary immune deficiency

Afzal,

MacDougall,

McGhee

2024

Current gene therapy for inborn errors of immunity have involved the use of gene addition approaches with viral delivery. This main strategy has had demonstrated success mainly in severe combined immune deficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Despite the increasing success of gene therapy, there are limitations of gene therapy, and, therefore, hematopoietic stem cell transplantation continues to be the preferred option. With improvements in viral delivery through next-generation lentiviral vectors and the advent of gene editing with CRISPR-Cas9, the efficacy and safety of gene therapy may soon surpass hematopoietic stem cell transplantation. Furthermore, these advances improve the viability of gene therapy for inborn errors of immunity primarily through decreased risk of transplantation-related complications. Therefore, despite current limitations, gene therapy for inborn errors of immunity is poised to continue to expand to more patients and indications.