Gene Therapy Approaches to Immunodeficiency

Abstract

Transfer of gene-corrected autologous hematopoietic stem cells in patients with primary immunodeficiencies has emerged as a new therapeutic approach. Patients with various conditions lacking a suitable donor have been treated with retroviral vectors and a gene-addition strategy. Initial promising results were shadowed by the occurrence of malignancies in some of these patients. Current trials, developed in the last decade, use safer viral vectors to overcome the risk of genotoxicity and have led to improved clinical outcomes. This review reflects the progresses made in specific disorders, including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome.

X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective

“…Over the last few years, there have been great strides developing effective and safe hematopoietic stem cell gene therapy as a viable alternative to BM transplantation for a number of PIDs. Gene therapy also offers the advantages of reduced toxicity from conditioning as, in general, less chemotherapy is required and the use of autologous cells removes the risk of graft versus host disease which causes significant morbidity and mortality post HSCT ( 96 , 97 ). Although several first-generation gene therapy trials were marred by the integration of gammaretroviral vectors near proto-oncogenes leading to leukemia and myelodysplasia, newer self-inactivating ( 16 ) retroviruses and lentiviruses have been developed that use internal mammalian promoters to drive transgene expression.…”

Hematopoietic Stem Cell Gene Therapy for Inherited Monogenic Diseases and Its Implications for Future Gene Therapy Trials in Turkey

“…In the first clinical trial for WAS a γRV vector was used, which resulted in correction of the functional defect. However, 7 of the 9 treated patients developed leukemia, because of integrations in the LMO2, MDS1/EVI1, MN1 proto-oncogenes (Ghosh & Gaspar 2017). The use of a SIN-LV-WASp vector to treat an adult WAS patient and 10 children showed promising results with rapid engraftment and sustained clinical improvement in the absence of insertional mutagenesis, showing that LV-based gene therapy may be developed as an alternative treatment for WAS (Hacein-Bey Abina et al 2015, Morris et al 2017).…”