Ponente: Cristina Mesa Núñez (Advanced Therapies Unit, IIS-FJD and Division of Innovative Therapies in the Hematopoietic System, CIEMAT).
Leukocyte adhesion deficiency type I (LAD-I) is a primary immunodeficiency caused by an impaired neutrophil migration in response to bacterial infections. The genetic causes of LAD-I are mutations in the ITGB2 gene that encodes for CD18, the common subunit of β2 integrins. These heterodimers are involved in the trafficking and extravasation of leukocytes to inflamed areas. The severity of the LAD-I disease is associated with the percentage of CD18 expressing cells. Patients with less than 2% CD18+ cells suffer a severe disease with a very high mortality rate before the age of 2. The current curative treatment of these patients is the allogenic hematopoietic stem cell (HSC) transplantation from healthy donors. The ex vivo gene therapy (GT) of autologous HSCs has been proposed as a good therapeutic option for these patients when non-HLA-matched related donors are available. Our laboratory has previously shown that the LV:Chim.hCD18 carrying the human ITGB2 gene under the control of a myeloid Chimeric promoter efficiently expresses the therapeutic human CD18 protein in myeloid cells from CD18HYP mice, and restores the functionality of these cells. To complete the preclinical studies required for the development of a gene therapy trial in severe LAD-I patients, further preclinical studies have been now developed to confirm the safety and efficacy of the approach.