From Bench to Bedside: Preclinical Evaluation of a Self-Inactivating Gammaretroviral Vector for the Gene Therapy of X-linked Chronic Granulomatous Disease

Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.

Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?

“…It will certainly be essential to combine several different preclinical strategies (such as xenotransplantation and high-throughput integration site analysis) in order to ensure safety. 42 In this context, the in-depth monitoring of retroviral integration site (RIS) patterns will help us to develop safer clinical trials.…”

Periodontal and other oral manifestations of immunodeficiency diseases

“…Depending on the severity of disease, treatment is usually directed toward antibiotic management of infections, HCT, and/or immunotherapy with interferon gamma (IFN‐ γ ) administration, adoptive T‐cell treatment, and gene therapy (Armstrong‐James and Harrison, ; Cole et al , ; Stein et al , ). Cole et al determined that patients with CGD who were treated with HCT had better survival and less incidence of infections than those managed with antibiotic therapy alone (Cole et al , ).…”

Traps and hyper inflammation – new ways that neutrophils promote or hinder survival

“…The importance of Nox is evident from patients with chronic granulomatous disease (CGD), where Nox is defective or missing. These patients suffer from recurrent bacterial and fungal infections which can be treated in experimental approaches with the re-transfer of a functional Nox system in mice (Stein et al, 2013) and humans (Bianchi et al, 2009). In addition, MPO is able to halogenate the surface of pathogens in the presence of H 2 O 2 generated from Nox products, a reaction that starts immediately after closure of the phagosome .…”