Dyskeratosis congenita future: Hematopoietic stem cell transplantation or gene therapy?

Abstract

Dyskeratosis congenital (DC) is a rare, multi-organ cancer-prone inherited bone marrow failure syndrome (IBMFs) caused by defects in telomere biology. IBMFs manifest as ineffective and stressed hematopoiesis owing to germline mutations that cause the failure of hematopoietic stem cell progenitor cells. The clinical presentation is heterogeneous, and serious clinical complications include bone marrow failure, hematological and solid tumors. Bone marrow failure is the main cause of death, although pulmonary fibrosis, hepatic cirrhosis, and cancer significantly contribute to morbidity and mortality. Currently, there is no specific medical treatment for DC. Hematopoietic stem cell transplantation (HSCT) is the only definitive treatment to restore bone marrow function, although it does not correct other abnormalities. HSCT may be a treatment option in subjects affected by DC and bone marrow failure, but it is associated with a high risk of early and late mortality due to infections, organ damage, and secondary malignancies. However, because of the toxicity associated with this treatment and adverse outcomes of HSCT in DC compared to other IBMFs, improved therapies are recommended for DC patients. As a result, gene therapy techniques based on the genetic modification of autologous hematopoietic stem and progenitor cells (HSPCs) have been explored. This review aims to provide a brief description of the currently known clinical and genetic characteristics, disease progression, and diagnosis and discuss HSCT and emerging strategies for using HSPC gene therapy for DC.