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Researchers from St. Jude Children’s Research Hospital have identified the specific locations in DNA where the gene therapy for X-linked severe combined immunodeficiency disorder (SCID-X1), often referred to as “bubble boy disease,” integrates. Those affected by SCID-X1 carry a faulty gene that disrupts the production of immune cells. In 2019, gene therapy from St. Jude Children’s Research Hospital successfully revived the immune systems of numerous infants with this condition by introducing corrected gene copies.
An article detailing these findings was recently published in Science Advances. In their study, the researchers delved into understanding where these gene copies become part of the patient's DNA. They discovered that, from a 3D viewpoint, certain genomic hotspots or regions are the first to come into contact with the lentiviral vector as it enters the cell’s nucleus through a pathway known as a nuclear pore.
Describing this process, Stephen Gottschalk, M.D., from St. Jude’s Department of Bone Marrow Transplantation and Cellular Therapy, stated, “It’s like someone coming into a room and taking the first available seat near the door.” He continued, elaborating on the analogy: “The room is the nucleus. The seats are these DNA elements right near the door of the nuclear pore. That never occurred to me before this study, but it’s a very simple principle in the end.”
This recent study showcased that the locations where the gene therapy integrates into patient cells greatly impact the safety and efficiency of the procedure. Koon-Kiu Yan, Ph.D., from St. Jude’s Department of Computational Biology, mentioned, “We performed a comprehensive single-cell multi-omic analysis of this gene therapy to understand whether a functional copy of the corrected gene was in patient cells, to what extent the gene was expressed, and the chromatin organization at a single-cell level.” He elaborated on the new capabilities they developed: “Before this study, we could measure the general gene expression of a bulk group of cells. But with bone marrow samples from two patients, we saw at a single-cell level which genes were expressed in which cell types.”
By leveraging single-cell analysis and other methodologies, the team discovered that past gene therapy endeavors led to integration near or directly into oncogenes, increasing the risk of cancer. However, the lentiviral vector employed by St. Jude purposefully bypasses these risky areas, enhancing the safety of the treatment. This pattern was also seen in a lentiviral gene therapy used for creating chimeric antigen receptor (CAR) T cells, indicating this could be a universal occurrence.
Jiyang Yu, Ph.D., St. Jude Department of Computational Biology interim chair, in collaboration with Gottschalk, commented on the study's implications: “The single-cell analysis is like deep cartography, a map with a near pixel-perfect resolution. The large number of integration sites could be used as a safety reference for future lentiviral gene therapies.”
This research has paved the way for a more profound comprehension of variations in treatment responses, presenting opportunities for refining future gene therapies.
An article detailing these findings was recently published in Science Advances. In their study, the researchers delved into understanding where these gene copies become part of the patient's DNA. They discovered that, from a 3D viewpoint, certain genomic hotspots or regions are the first to come into contact with the lentiviral vector as it enters the cell’s nucleus through a pathway known as a nuclear pore.
Describing this process, Stephen Gottschalk, M.D., from St. Jude’s Department of Bone Marrow Transplantation and Cellular Therapy, stated, “It’s like someone coming into a room and taking the first available seat near the door.” He continued, elaborating on the analogy: “The room is the nucleus. The seats are these DNA elements right near the door of the nuclear pore. That never occurred to me before this study, but it’s a very simple principle in the end.”
This recent study showcased that the locations where the gene therapy integrates into patient cells greatly impact the safety and efficiency of the procedure. Koon-Kiu Yan, Ph.D., from St. Jude’s Department of Computational Biology, mentioned, “We performed a comprehensive single-cell multi-omic analysis of this gene therapy to understand whether a functional copy of the corrected gene was in patient cells, to what extent the gene was expressed, and the chromatin organization at a single-cell level.” He elaborated on the new capabilities they developed: “Before this study, we could measure the general gene expression of a bulk group of cells. But with bone marrow samples from two patients, we saw at a single-cell level which genes were expressed in which cell types.”
By leveraging single-cell analysis and other methodologies, the team discovered that past gene therapy endeavors led to integration near or directly into oncogenes, increasing the risk of cancer. However, the lentiviral vector employed by St. Jude purposefully bypasses these risky areas, enhancing the safety of the treatment. This pattern was also seen in a lentiviral gene therapy used for creating chimeric antigen receptor (CAR) T cells, indicating this could be a universal occurrence.
Jiyang Yu, Ph.D., St. Jude Department of Computational Biology interim chair, in collaboration with Gottschalk, commented on the study's implications: “The single-cell analysis is like deep cartography, a map with a near pixel-perfect resolution. The large number of integration sites could be used as a safety reference for future lentiviral gene therapies.”
This research has paved the way for a more profound comprehension of variations in treatment responses, presenting opportunities for refining future gene therapies.