Hematopoietic Stem Cell BCL11A Enhancer Gene Editing for Severe β-Hemoglobinopathies

Description

This is a non-randomized, single center, open-label, pilot safety and feasibility study involving a single infusion of autologous bone marrow derived CD34+ hematopoietic stem cells (HSPCs) electroporated with BCL11A enhancer targeting Cas9 ribonucleoprotein. Accrual will be a maximum of 14 evaluable subjects with sickle cell disease (SCD) or β-thalassemia. The study will enroll 7 evaluable subjects within each disease group: SCD and β-thalassemia. The study will have two strata within each diagnosis group.

SCD

Ages ≥18-40 years: Stratum 1a (n=3-7)

Ages ≥13-18 years: Stratum 2a (n=0-4)

β-thalassemia

Ages ≥18-40 years: Stratum 1b (n=3-7)

Ages ≥13-18 years: Stratum 2b (n=0-4)

After meeting eligibility criteria, patients will be enrolled. Patients with SCD will receive blood transfusions for a period of 3 months prior to hematopoietic stem cell collection, with a goal of achieving a Hemoglobin S (HbS) level of ≤ 30% by the time of mobilization. All patients will undergo peripheral stem cell mobilization and have their cells collected by apheresis. The collected ells of each subject will be split into 2 portions; one portion for transduction with the lentiviral vector, and one portion set aside as a back-up product in the event a rescue treatment is needed. Patients may undergo multiple rounds of collection if sufficient numbers of cells are not obtained with the first collection.

Patients will undergo a standard work-up for autologous bone marrow transplantation prior to proceeding with conditioning and infusion of their gene-edited cells. Patients will receive myeloablative conditioning with busulfan administered on days -5 to -2, prior to the infusion of edited cells. The edited cells will be infused intravenously.

Patients will be followed for 24 months after the infusion of their gene edited cells.