Evolution of Gene Therapy for Inborn Errors of Immunity

Inborn errors of immunity comprise more than 500 monogenic defects that predispose affected individuals to life-threatening infections, autoimmunity, and lymphoproliferation. The diagnosis and treatment of inborn errors of immunity have significantly evolved in the past few decades.1 Currently, a hematopoietic stem cell transplant (HSCT) is the definitive treatment of many IEIs. However, an HSCT carries risks, such as graft-vs-host disease and decreased survival rates in the absence of an HLA-matched donor. Gene therapy (GT) offers a promising alternative by targeting and correcting specific genetic mutations. Ex vivo GT entails genetically modifying cells, typically CD34+ hematopoietic stem and progenitor cells (HSPCs), outside the body and then transplanting the cells back into patients, whereas in vivo GT delivers genetic material directly to target cells within the body.