Early trials of hematopoietic stem cell (HSC) gene therapy reported clear patient benefits, but the trials also highlighted the limitations and risks of the first-generation integrating vectors. In order to improve the safety and efficacy of gene transfer, a new integrating vector system was developed starting from HIV. The outcome of these efforts was lentiviral vectors that showed robust gene transfer and improved safety in several preclinical models. They have since become one of the most widely used gene transfer tools in biomedical research. More recently, upon entering clinical testing in HSC and T-cell gene therapy, lentiviral vectors are providing a long-sought hope of cure for some human diseases without satisfying treatments. Current results from ongoing HSC gene therapy trials for several different indications show substantial therapeutic benefits. The inherited disorders of hemoglobin represent the most common monogenic disease, and it has been estimated that around 7 percent of humans are carrying one of the mutations responsible for these disorders. Patients affected by thalassemia major and sickle cell anemia have stably become transfusion-independent and completely asymptomatic upon lentiviral HSC gene therapy. Near-complete genetic engineering of hematopoiesis has been achieved without clinical or molecular signs of adverse effects of vector insertion to the latest follow up, reaching up to nine years in the earliest treated patients. In-depth analysis of the genomic landscape of vector insertion shows a picture of polyclonal multi-lineage reconstitution of hematopoiesis without emergence of expanding clones, consistent with efficient engraftment of transduced HSC. These findings validate the predictions from preclinical models and support improved efficacy and safety of lentiviral vectors as compared to earlier generation vectors. If safety and efficacy are confirmed in more patients and upon longer follow-up, autologous HSC gene therapy may eventually become a preferred option over allogenic HSC transplantation.
Dr. Luigi Naldini will review the development of lentiviral vectors and the molecular analyses showing safe and efficient HSC gene transfer in preclinical and clinical studies. Early in his career, he described the use of HIV-derived hybrid lentiviral vectors for gene transfer into non-dividing cells. This work laid the foundation for the currently broad use of lentiviral vectors.
Dr. Marina Cavazzana will review the current stage of clinical application and benefit of HSC gene transfer by lentiviral vectors. She is a dynamic and innovative investigator who has spearheaded translational and clinical advances achieved in hematopoietic stem cell gene therapy for multiple inborn immune, hematopoietic, and metabolic disorders.
Kenneth C. Anderson
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