Using CRISPR to Treat Sickle Cell Disease

In 2023, the FDA officially approved Casgevy for the treatment of sickle cell disease (SCD). This marked not only a milestone treatment for SCD but also an immense step forward in the use of genome-editing technology, setting a new precedent in the field of gene therapy.

Casgevy utilizes the revolutionary CRISPR-Cas9 technology. CRISPR-Cas9 was adapted from a naturally occurring system that bacteria use as an immune defense. When infected with viruses, bacteria incorporate small pieces of viral DNA into their own genome, creating segments known as CRISPR arrays. These function as immune memory. If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays that recognize and attach to specific regions of the viral DNA. At this point, the bacteria use the Cas9 enzyme to cut the viral DNA, disabling the virus.

Inspired by this genome editing system, researchers set out to edit DNA. They create small RNA molecules with a short “guide” sequence that bind to a specific target in a cell’s DNA. The molecules also attach to Cas9. When introduced into cells, the guide RNA will bind to the intended DNA sequence, and Cas9 will cut at the target site. Once DNA is cut, researchers can either make changes by replacing the segment with a customized sequence or use the cell’s own DNA repair system to add or delete as needed.

Sickle cell disease is caused by a mutation in the beta chain of the adult hemoglobin (HbA). HbA is composed of two alpha and two beta subunits. The mutation in the beta subunit changes a glutamate to a valine. Glutamate is charged and hydrophobic. When it is replaced with the hydrophobic, neutral valine, it creates a “sticky” patch that causes aggregation, leading to the characteristic sickle shape.

Researchers wanted to utilize this new CRISPR technology to combat sickle cell anemia, but CRISPR targets DNA segments, not amino acid mutations in formed proteins. Therefore, they had to consider which DNA segment produces beta hemoglobin, and what options they had to turn off its production. But HbA is composed of both alpha and beta hemoglobin subunits. How could they avoid producing beta hemoglobin without essentially shutting down all hemoglobin production?

When babies are forming in the womb, they need a mechanism to pull oxygen out of the mother’s circulating blood in the placenta. If fetal blood had the same hemoglobin as the mother’s, its oxygen affinity would not be high enough to cause the oxygen to preferentially go to the baby. So, before birth, instead of producing HbA, developing fetuses produce HbF, a form of hemoglobin that consists of 2 alpha and 2 gamma subunits. This part is key; fetal hemoglobin does not contain any beta subunits. This means that if researchers could find a way to edit DNA with CRISPR to prevent the production of beta subunits and promote the production of gamma subunits past birth, adults with sickle cell disease could live healthy lives with HbF instead of sickled HbA.

They found their perfect target in a gene called BCL11A. This gene causes the shift from HbF to HbA by promoting the production of beta subunits and blocking gamma subunit production. It normally codes for a transcriptional repressor protein of the same name that binds to and turns off gamma-globin genes. Using CRISPR, Casgevy edits and turns off the BCL11A gene, turning fetal hemoglobin production back on, boosting a healthy form of hemoglobin that cannot sickle.

Gene-editing technologies such as CRISPR enable creative solutions for medical conditions that could never have been achieved before. Precision DNA editing opens up many exciting possibilities for future research.

Thank you for reading,

Ashby Glover

Sources

Casgevy. “Be Informed: How CASGEVY^® Works.” Accessed April 4, 2026. https://www.casgevy.com/sickle-cell-disease/how-casgevy-works 

Garrott W. Christoph, James Hofrichter, William A. Eaton. “Understanding the Shape of Sickled Red Cells.” Biophysical Journal 88, no. 2 (2005): 1371-1376. doi: 10.1529/biophysj.104.051250.

National Library of Medicine. “What are genome editing and CRIPSR-Cas9?” Accessed April 4, 2026. https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/

U.S. Food and Drug Administration. “FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease.” December 8, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease