Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease

• DOI: 10.1016/j.ymthe.2024.07.022
• Publication Date: 2024-07-31T02:11:36Z
• Authors: Varun Katta; Kiera O’Keefe; Yichao Li; Thiyagaraj Mayura...; Cicera R. Lazzarotto; Rachael K. Wood; Rachel M. Levine; Alicia Powers; Kalin Mayberry; Garret Manquen; Yu Yao; Jingjing Zhang; Yoonjeong Jang; Nikitha Nimmagadda; Erin A. Dempsey; GaHyun Lee; Naoya Uchida; Yong Cheng; Frank Fazio; Tim Lockey; Mike Meagher; Akshay Sharma; John F. Tisdale; Sheng Zhou; Jonathan S. Yen; Mitchell J. Weiss; Shengdar Q. Tsai
• Keywords: Cell therapy

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem transplantation associated with immune toxicities. Genome editing of patient cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach treat SCD. Although the FDA released guidelines for evaluating genome risks, it remains unclear how best pre-clinical assessment genome-edited products. Here, we describe rigorous development therapeutic γ-globin gene promoter strategy that supported investigational new drug application cleared by FDA. We compared BCL11A enhancer targets, identified potent HbF-inducing lead candidate, tested our mobilized CD34