Future of Therapy for Inborn Errors of Immunity

Abstract

Over the past 20 years, the rapid evolution in the diagnosis and treatment of primary immunodeficiencies (PI) and the recognition of immune dysregulation as a feature in some have prompted the use of "inborn errors of immunity" (IEI) as a more encompassing term used to describe these disorders [1, 2] . This article aims to review the future of therapy of PI/IEI (referred to IEI throughout this paper). Historically, immune deficiencies have been characterized as monogenic disorders resulting in immune deficiencies affecting T cells, B cells, combination of T and B cells, or innate immune disorders. More recently, immunologists are also recognizing a variety of phenotypes associated with one genotype or similar phenotypes across genotypes and a role for incomplete penetrance or variable expressivity of some genes causing inborn errors of immunity [3]. The IUIS classification of immune deficiencies (IEIs) has evolved over time to include 10 categories, with disorders of immune dysregulation accounting for a new subset, some treatable with small molecule inhibitors or biologics. [1] Until recently, management options were limited to prompt treatment of infections, gammaglobulin replacement, and possibly bone marrow transplant depending on the defect. Available therapies have expanded to include small molecule inhibitors, biologics, gene therapy, and the use of adoptive transfer of virus-specific T cells to fight viral infections in immunocompromised patients. Several significant contributions to the field of clinical immunology have fueled the rapid advancement of therapies over the past two decades. Among these are educational efforts to recruit young immunologists to the field resulting in the growth of a world-wide community of clinicians and investigators interested in rare diseases, efforts to increase awareness of IEI globally contributing to international collaborations, along with advancements in diagnostic genetic testing, newborn screening, molecular biology techniques, gene correction, use of immune modulators, and ex vivo expansion of engineered T cells for therapeutic use. The development and widespread use of newborn screening have helped to identify severe combined immune deficiency (SCID) earlier resulting in better outcomes [4]. Continual improvements and accessibility of genetic sequencing have helped to identify new IEI diseases at an accelerated pace [5]. Advances in gene therapy and bone marrow transplant have made treatments possible in otherwise fatal diseases. Furthermore, the increased awareness of IEI across the world has driven networks of immunologists working together to improve the diagnosis and treatment of these rare diseases. These improvements in the diagnosis and treatment of IEI noted over the past 20 years bring hope for a better future for the IEI community. This paper will review future directions in a few of the newer therapies emerging for IEI. For easy reference, most of the diseases discussed in this paper are briefly described in a summary table, in the order mentioned within the paper (Appendix).

Keywords: Fusion protein; Gene therapy; Inborn errors of immunity; Monoclonal antibodies; Newborn screening; Primary immunodeficiency; Small molecule inhibitors.