Clinical and Molecular Characterization of TCIRG1-Related Autosomal Recessive Osteopetrosis with Current Therapeutic...

Background/Objectives:TCIRG1-associated infantile osteopetrosis is a severe hereditary disorder caused by impaired osteoclast function, leading to osteosclerosis, hematological abnormalities, neurological complications, and early mortality. Early diagnosis and intervention are critical. Methods: A literature-based analysis was performed on clinical manifestations, outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), immunomodulatory therapy, and experimental gene therapy and cell-based approaches, including lentiviral vectors and patient-derived induced pluripotent stem cells (iPSCs). Results: Allogeneic HSCT is the only established curative therapy, restoring osteoclast function and preventing severe complications. Early transplantation with HLA-matched donors and myeloablative conditioning provides optimal outcomes. Interferon γ1b can transiently enhance osteoclast activity but is not curative and shows variable efficacy. Preclinical studies demonstrate that lentiviral TCIRG1 delivery and transgenic correction in patient-derived iPSCs restore osteoclast function and bone resorption, with stable gene expression and minimal toxicity. Base and prime editing approaches offer potential for precise correction of single-nucleotide TCIRG1 variants, minimizing risks associated with double-strand DNA breaks. Conclusions: Allogeneic HSCT remains the standard therapy for TCIRG1-associated infantile osteopetrosis. Gene therapy and cell-based strategies represent promising adjuncts or alternatives, potentially avoiding immune-related complications and expanding therapeutic options. Further studies are needed to ensure safety, stable engraftment, and long-term efficacy, supporting translation of gene therapy into clinical practice.