“A person living with sickle cell disease at Odessa Brown Children's Clinic in Seattle, Washington, who recently emigrated from Africa, spoke about their experience with the disease. They described living with the disease as being defined by constant health worries, not being able to do as much as other people, and putting in extra work just to stay and feel as healthy as possible.”
Sickle cell disease (SCD) is a lifelong, debilitating genetic blood disorder that disproportionately affects people of African descent, but also touches millions globally from Hispanic, Middle Eastern, southern European, and Asian Indian backgrounds. Caused by a single-point mutation in the HBB gene, it results in red blood cells taking on a distorted sickle shape, leading to chronic anemia, painful vaso-occlusive crises, and organ damage.
Despite being one of the first genetic diseases ever described, first identified in 1910 by Dr. James B. Herrick as a Grenadian medical student, it remained poorly understood until the mid-20th century. In 1957, scientists discovered that the disease was caused by a single amino acid substitution in the β-globin chain of hemoglobin. This landmark made SCD the first molecularly characterized genetic disorder. By 1977, the sequencing of the sickle gene ushered in a new era of understanding gene mutations and opened the door to potential therapeutic interventions.
The need for new treatments has never been more urgent. Between 2000 and 2021, the number of babies born with SCD globally rose by nearly 14%, reaching over 515,000 births annually. In the same period, the number of people living with the disease increased by over 41%. Alarmingly, the global mortality burden in 2021 reached an estimated 376,000 deaths many of them in children under the age of five, particularly in sub-Saharan Africa and South Asia.
For decades, hydroxyurea approved in 1998 offered one of the few available therapies, improving outcomes for some patients. However, it is not curative, and its accessibility remains uneven. The global scientific community reached a turning point in 2023 when the FDA approved Casgevy and Lyfgenia, the first cell-based gene therapies for SCD, targeting patients aged 12 and older. These approvals marked a historic shift in treatment, with additional promising trials now underway, including intravenous L-arginine therapy aimed at reducing acute pain episodes in children.
Our research is building on this momentum by advancing a next-generation therapeutic strategy focused on reactivating fetal hemoglobin (HbF) , an oxygen-carrying form of hemoglobin that naturally protects infants from the complications of SCD but declines after birth. HbF can compensate for the defective β-globin and reduce sickling of red blood cells. Both SCD and β-thalassemia, another inherited blood disorder, can be significantly ameliorated by increasing HbF levels.
Our approach targets BCL11A, a key transcriptional repressor of γ-globin (the component of HbF). Instead of attempting to directly correct the HBB gene mutation, we employ CRISPR-Cas9 gene editing to disrupt the erythroid-specific enhancer within the BCL11A gene. This leads to a targeted reduction of BCL11A expression in red blood cell precursors, thereby reactivating γ-globin production. This method bypasses some of the complexities and risks of other editing approaches and has shown significant promise in early clinical studies.
From the discovery of the sickled cell in 1910 to the approval of gene therapies in 2023, the story of SCD is one of persistence, innovation, and progress. At cellogen, we are proud to be part of the next chapter one where molecular medicine and global access intersect to bring lasting hope to millions.
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