Can Gene Therapy Help Treat Sickle Cell Disease?

Emily Nettesheim - June 23, 2020

Last Friday, June 19, was World Sickle Cell Day, an international awareness day with the goal to increase public knowledge and understanding of sickle cell disease.

Dubbed by the United Nations as “one of the world’s foremost genetic diseases,” sickle cell disease is believed to affect nearly 20 million people across the globe. The sickle cell trait has higher prevalence in people of African, Caribbean, and Hispanic descent. In the United States, one in every 365 African or Caribbean-Americans and one in every 16,300 Hispanic-American births are children affected by sickle cell disease. In the United Kingdom, it is estimated that one in every 76 births are carriers for the sickle cell trait, and approximately 15,000 people have sickle cell disease.

There are six types of sickle cell disease, which differ based on the inheritance pattern and the exact mutation present in the beta-globin, or HBB, gene. The six types often result in similar physical symptoms with a range in severity. Beta-globin is one of the subunits which makes up the adult hemoglobin protein, a component of red blood cells, and plays a vital role in the binding and transportation of oxygen throughout the body. Across all types, the characteristic C or sickle-shaped blood cells are present, leading to anemia, jaundice, and fatigue, with long- term complications including infections, hindered growth, and organ damage. In addition to these chronic symptoms, the sickle shape of the blood cells can cause vessel blockage, resulting in extreme pain and swelling near the clot.

Currently, the best long-term treatment for sickle cell patients is a bone marrow transplant. However, there are many complications related to getting a transplant that can prevent patients from receiving treatment, such as inability to find a matching donor. Across the country, clinical trials are underway to assess new treatments for sickle cell disease, including some gene and cell therapies. One method of treatment being explored involves the knockdown of a fetal hemoglobin gene, BCL11A. BCL11A is a transcription factor necessary for expression of gamma-globin, a component of fetal hemoglobin. Therefore, knockdown of BCL11A allows for expression of fetal hemoglobin, which is unable to form a sickle shape, even in sickle cell patients.

Boston Children’s Hospital is a participant in the current bluebird bio clinical trial utilizing this method and provided a promising update on their pilot trial at the 2019 ASH Annual Meeting. The study included eight patients, ages 7-36, mostly of type HbSS. The treatment involved harvesting CD34-positive cells from the patients, then transducing the cells with an shmiR lentiviral vector targeting BCL11A. Transduced CD34-positive cells were then infused back into the patient. Six months following infusion, clinicians saw stable copy numbers, effective knockdown of BCL11A protein, and induction of fetal hemoglobin. No adverse events were noted with the study as related to the cell product, and none of the patients had crisis events following treatment, suggesting that BCL11A is a promising target for future gene and cell therapies.

With exciting advances in the gene and cell therapy field, the future of treatment looks bright for those suffering from sickle cell disease. Look for a more in-depth profile on ASGCT’s Global Outreach Committee and what they are doing to help fight the disease in September for Sickle Cell Awareness Month.

Emily Nettesheim is a member of the ASGCT Communications Committee.



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