Hematopoietic Stem Cell Gene Therapy: Assessing the Relevance of Preclinical Models

Abstract

The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs.

Validation and Long-Term Follow Up of CD33 Off-Targets Predicted In Vitro and In Silico Using Error-Corrected Sequencing in Rhesus Macaques

“…This ISP method has been used previously in our studies and was successful in predicting bona fide off-targets in rhesus cells 16 . We focused on the rhesus macaque autologous transplantation model for study based on similarities of rhesus and human hematopoiesis and the strong predictive value of this model for hematopoietic stem cell gene therapies 17,18 . Hematopoietic stem and progenitor cells are electroporated with RNPs and reinfused into the autologous animal following conditioning irradiation 5 ( Figure S1).…”

MiRNA-16 inhibited oral squamous carcinoma tumor growth in vitro and in vivo via suppressing Wnt/β-catenin signaling pathway

“… 1 In recent years, there has been an increasing focus on gene therapy, which has been applied in primary immunodeficiencies, 2 hemoglobin disorders, 3 coagulation disorder hemophilia B, 4 inherited neurological disorders, and cancer immunotherapy. 5 – 7 However, gene therapy treatment for oral carcinoma has been seldom investigated.…”

Collection of hematopoietic CD34 stem cells in rhesus macaques using Spectra Optia

“…In clinical practice apheresis has surpassed bone marrow harvest as the procedure of choice for collection of HSCs . These large animals are particularly relevant translational models because their hematopoietic cells have a high degree of cross reactivity with human reagents and responsiveness to human cytokines . The use of rhesus macaques in HSC transplant models, however, is challenging due to their relative small size (typically 4–10 kg), which makes apheresis a demanding procedure with safety implications.…”