Mutations in DOCK8 result in a rare but serious disease called autosomal recessive hyper-IgE syndrome (AR-HIES), a combined immunodeficiency manifesting as severe recurrent infections as well as multiple comorbidities including allergic disease, autoimmunity, and malignancies. Allogeneic hematopoietic stem cell transplant (HSCT) is currently the only definitive therapy for AR-HIES. It is recommended for all patients, even those with severe disease burden, given the high morbidity and mortality associated with this particular immunodeficiency. The curative nature of allogeneic HSCT suggests that ex vivo genome modification of autologous HSC may be an effective treatment for AR-HIES with potentially fewer risks. The aim of this project was to compare the efficacy of viral vector mediated gene therapy to site-specific gene editing at the DOCK8 locus. Our group evaluated several lentiviral vectors carrying a corrective copy of the DOCK8 cDNA to deliver first as a test in cell lines followed by evaluation in primary hematopoietic stem cells. In addition, we have designed a CRISPR based approach to evaluate gene editing for this disease. Both avenues of gene therapy are still in development with work ongoing to identify the safest and most efficacious therapeutic candidate for those with AR-HIES.
