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Mouse models in hematopoietic stem cell gene therapy and genome editing.

ABSTRACT: Gene therapy has become an important treatment option for a variety of hematological diseases. The biggest advances have been made with CAR T cells and many of those studies are now FDA approved as a routine treatment for some hematologic malignancies. Hematopoietic stem cell (HSC) gene therapy is not far behind with treatment approvals granted for beta-hemoglobinopathies and adenosine deaminase severe combined immune deficiency (ADA-SCID), and additional approbations currently being sought. With the current pace of research, the significant investment of biotech companies, and the continuously growing toolbox of viral as well as non-viral gene delivery methods, the development of new ex vivo and in vivo gene therapy approaches is at an all-time high. Research in the field of gene therapy has been ongoing for more than 4 decades with big success stories as well as devastating drawbacks along the way. In particular, the damaging effect of uncontrolled viral vector integration observed in the initial gene therapy applications in the 90s led to a more comprehensive upfront safety assessment of treatment strategies. Since the late 90s, an important read-out to comprehensively assess the quality and safety of cell products has come forward with the mouse xenograft model. Here, we review the use of mouse models across the different stages of basic, pre-clinical and translational research towards the clinical application of HSC-mediated gene therapy and editing approaches.

SUBMITTER: Radtke S

PROVIDER: S-EPMC7050335 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS:We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS:A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS:Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).

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Mouse models in hematopoietic stem cell gene therapy and genome editing.

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