Disorders of hemoglobin production are the most common inherited disorders of hematopoiesis, and are a cause of immense human morbidity and economic loss across the globe. Recent advances in gene-editing technology have demonstrated the potential to directly manipulate the endogenous globin locus in human hematopoietic stem and progenitor cells. However, significant barriers remain for translation of gene editing as an effective therapeutic approach to disorders of globin production, including 1) definition of gene-edited globin locus architectures that support high levels of non-sickling globin production, 2) maintenance of multi-lineage reconstitution capability of gene-edited HSPC, and 3) development of methods for efficient engraftment and selection of gene-edited HPSC. In this application, we propose two coordinated specific aims that collectively address these barriers.
Specific Aim 1 will utilize recently published methods for efficient HSPC gene editing to define globin locus architecture(s) that support high levels of erythroid specific globin production and that enable post-engraftment selection of gene-edited cells.
Specific Aim 2 will evaluate engraftment and selection protocols for gene-edited HSPC in a clinically relevant macaque autologous transplant model. Collectively, the proposed studies will define an optimized globin gene editing procedure along with a IND-enabling pre-clinical data set that will serve as a foundation for translation of therapeutic gene editing for disorders of ?-globin synthesis to phase I clinical testing in humans.
Disorders of hemoglobin production are the most common inherited disorders of the blood and are a cause of an immense burden to human health and economic loss across the globe. Recent advances in so-called gene- editing technology have demonstrated the potential to directly correct the globin locus in the patient's blood cells. In this application we propose to tackle current limitations to this approach and to the successful translation of this strategy to the clinic and to patients.
| Humbert, Olivier; Peterson, Christopher W; Norgaard, Zachary K et al. (2018) A Nonhuman Primate Transplantation Model to Evaluate Hematopoietic Stem Cell Gene Editing Strategies for ?-Hemoglobinopathies. Mol Ther Methods Clin Dev 8:75-86 |
| Lux, Christopher T; Scharenberg, Andrew M (2017) Therapeutic Gene Editing Safety and Specificity. Hematol Oncol Clin North Am 31:787-795 |
