Cristina Mesa Núñez, Spain
Instituto de Investigación Sanitaria Fundación Jiménez Díaz and Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas Advanced Therapies UnitPresenter of 1 Presentation
PRECLINICAL STUDIES FOR THE INITIATION OF A GENE THERAPY TRIAL IN PATIENTS WITH SEVERE LEUKOCYTE ADHESION DEFICIENCY TYPE I (LAD-I)
Abstract
Background and Aims
Leukocyte Adhesion Deficiency Type I (LAD-I) is a primary immunodeficiency caused by mutations in the ITGB2 gene encoding for CD18, the common subunit of β2 integrins, required for normal leukocyte extravasation to infection sites. LAD-I patients suffer from life-threatening bacterial and fungal infections that cannot be properly resolved. Although allogenic hematopoietic transplantation is the preferred therapy, gene therapy is considered a good option for LAD-I patients.
Methods
Aiming the lentiviral-mediated gene therapy of LAD-I patients, we developed a lentiviral vector (LV) in which expression of hCD18 is driven by the CatG/cFES chimeric promoter, preferentially active in myeloid cells. The efficacy of this LV to correct the disease in CD18HYP mice was previously demonstrated.
Results
Here we show that the infusion of gene-modified HSCs in knock-out LAD-I mice corrected the phenotype of these animals. The efficacy of the LV-mediated gene therapy occurred in the absence of any hematotoxic or genotoxic effect. Further studies with a GMP-produced Chim.hCD18-LV allowed us to optimize the transduction of human CD34+ cells using a combination of transduction enhancers. Finally, validation runs of the GMP-transduction procedure were performed, demonstrating robust and reproducible transduction efficiencies of CD34+ cells that retained their repopulation ability in NSG transplanted mice.
Conclusions
Our preclinical studies showed the efficacy of the proposed LV-mediated gene therapy in LAD-I mouse models and demonstrated the efficient transduction of human CD34+ cells under GMP conditions. A Phase I Clinical Trial has been approved for the treatment of patients with severe LAD-I.