Individuals with severe sickle cell disease, who are between 18 and 50 years old, may be able to participate. A number of screening tests will be done to determine if subjects can participate. These include review of your past medical history, physical exam, blood and urine tests, pregnancy test, heart ultrasound, electrocardiogram, pulmonary function test, kidney function test, questionnaires, and magnetic resonance imaging (MRI) of the heart and liver. If eligible, blood stem cells will be collected by apheresis.A gene in thesestem cells will thenbe edited to help the stem cells make more fetal hemoglobin. Higher levels of fetal hemoglobin can improve red blood cell sickling. You will then be hospitalized and chemotherapy will be given to empty out the bone marrow. The stem cells, with themodifiedgene, will then be given back to you. You will be followed for side effects and to see if themodifiedgene helps you make healthyred blood cells.

This Phase 2 clinical research study is evaluating the safety and effectiveness of a once-daily oral investigational medicine that may improve anemia and reduce the need for red blood cell (RBC) transfusions among some patients who are chronically transfused. All participants enrolled in the study will receive the investigational medication.

We are currently enrolling individuals who meet the following criteria:*

• Regular RBC transfusions to prevent stroke or recurrence of stroke (Cohort A)
• Thalassemia and receiving regular RBC transfusions (Cohort B)
• Thalassemia and not receiving regular RBC transfusions (Cohort C)

There are additional eligibility requirements, which the investigator will explain to you.

We are trying to learn more about the ways in which adolescents (12-17 years) are involved in decision making related to their chronic condition. We are hoping to partner with families who are planning to attend or recently attended a visit in the Comprehensive Sickle Cell Center, Diabetes Center for Children, Center for Inflammatory Bowel Disease, or the Division of Rheumatology at CHOP.

If you and your child are able to help us, you will each be asked to complete a questionnaire about your experiences during a recent clinic visit. Additionally, a random selection of parents and teens will be asked to complete an interview with our team. All participants will be compensated for their participation in this study.

It is essential that we speak to families before or immediately following their scheduled visit at CHOP.