Establishment of Preclinical Trial of Lentiviral Gene Transfer to Prevent Bloom Syndrome-Related Hematological Malignancy

Abstract

Bloom syndrome is a rare hereditary DNA repair disorder associated with a high risk of cancer. Patients with Bloom syndrome have a markedly increased risk of developing various cancers, particularly hematological malignancies, making cancer the leading cause of death in these individuals. Therefore, we hypothesized that the prevention of cancer could be a key point for these patients. This review focuses on designing a preclinical study exploring the potential of gene therapy to address this significant clinical challenge. Three issues were established for this preclinical study, and research is ongoing to solve these issues. The first was the development of an envelope-modified lentivirus designed to treat DNA repair disorders. This lentivirus has been engineered to effectively deliver therapeutic genes to cells affected by Bloom syndrome, and cytokine stimulation induces apoptosis in hematopoietic stem cells (HSCs). Second, we demonstrated that lentivirus-mediated gene transfer corrects the expression and function of BLM gene in bone marrow cells derived from a Bloom syndrome mouse model. These experiments indicated that the therapeutic gene delivered by the lentivirus can correct cellular defects associated with Bloom syndrome, thereby restoring normal cell function. Finally, we investigated the ability of gene therapy to prevent the development of radiation-induced tumors in BLM mice. By detailing the development and testing of this innovative gene therapy, this review demonstrated the potential of such treatments to transform the clinical management of DNA repair disorders, which could be translated into improved survival and quality of life in patients with Bloom syndrome.journal articl