Marnetegragene autotemcel

Severe leukocyte adhesion deficiency-I (LAD-I) is a genetic disorder caused by biallelic variants in the ITGB2 gene, leading to deficient expression of CD18, a crucial subunit of β2 integrins required for leukocyte adhesion and extravasation to sites of infection and inflammation. Marnetegragene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy that works by adding functional copies of the ITGB2 gene into the patient's autologous hematopoietic stem cells. This is achieved through ex vivo transduction of CD34+ enriched HSCs with LV-RP-201 which is a replication-incompetent, self-inactivating lentivirus vector encoding for the CD18 β-subunit of human β2 integrins (ITGB2).

Following marnetegragene autotemcel infusion, the transduced CD34+ HSCs engraft in the bone marrow and subsequently differentiate into various cell types, including leukocytes. These differentiated leukocytes are then capable of expressing functional CD18 protein. The presence of functional CD18 protein enables the formation of the CD18/CD11a heterodimer, also known as Leukocyte Function-Associated Antigen-1 (LFA-1), which then facilitates proper leukocyte adhesion to endothelial surfaces and their extravasation to infectious and inflammatory sites, thereby addressing the underlying defect in LAD-I.