Title:Gene Therapy for Chronic Granulomatous Disease: Current Status and Future Perspectives
Volume: 14
Issue: 6
Author(s): Kerstin B. Kaufmann, Maria Chiriaco, Ulrich Siler, Andrea Finocchi, Janine Reichenbach, Stefan Stein and Manuel Grez
Affiliation:
关键词:
慢性肉芽肿病（CGD）、移植物移入、基因疗法、炎症， NADPH氧化酶，原发性免疫缺陷， ROS 。
摘要: Several Phase I/II clinical trials aiming at the correction of X-linked CGD by gene transfer into hematopoietic
stem cells (HSCs) have demonstrated the therapeutic potential of gene modified autologous HSCs for the treatment of
CGD. Resolution of therapy-resistant bacterial and fungal infections in liver, lung and spinal canal of CGD patients were
clearly documented in all trials. However, clinical benefits were not sustained over time due to the failure of gene transduced
cells to engraft long-term. Moreover, severe adverse effects were observed in some of the treated patients due to insertional
mutagenesis leading to the activation of growth promoting genes and to myeloid malignancy. These setbacks
fostered the development of novel safety and efficacy improved vectors that have already entered or are about to enter the
clinics. Meanwhile, ongoing research is constantly refining the CGD disease phenotype, including the definition of factors
that may explain the unique engraftment phenotype observed in CGD gene therapy trials. This review provides a condensed
overview on the current knowledge of the molecular pathomechanisms and clinical manifestations of CGD and
summarizes the lessons learned from clinical gene therapy trials, the preclinical progress in vector design and the future
perspectives for the gene therapy of CGD.
