Flipping the Switch and Turning On New Sickle Cell and Thalassemia Therapies

A new chapter is unfolding for patients with sickle cell disease and beta-thalassemia: breakthroughs in gene regulation are transforming how these conditions are treated. Emerging approaches focus on turning fetal hemoglobin back on by blocking the molecular “off switch” that normally silences it after birth. These directly target the regulatory pathways controlling hemoglobin expression. With the potential to reduce painful crises, organ damage and transfusion dependence, precision-driven gene and epigenetic therapies have the potential to offer a more targeted path for the millions affected worldwide.

Think of it like a nursery light switch. When a baby is born and starts to grow, it’s as if the sun comes up. Once this happens, you don’t need the overhead light anymore, and you flip the switch off. For those with sickle cell disease or beta-thalassemia, the “sun” of healthy adult hemoglobin never fully rises. Thus, there is a lack of working adult hemoglobin. In this case, there’s no reason to turn off the light. In fact, the best option might be to break the switch so the light—fetal hemoglobin—keeps shining.

Understanding the Science

Hemoglobin is the essential protein that enables red blood cells to carry oxygen throughout our bodies. There are two main types: fetal hemoglobin, which is highly effective at capturing and delivering oxygen before birth and in infants and adult hemoglobin, which gradually takes over as children grow. The body uses a genetic switch to turn off fetal hemoglobin production after infancy. This ensures adult hemoglobin becomes dominant.

In sickle cell disease and beta-thalassemia, mutations in the adult hemoglobin gene disrupt this process. Red blood cells become stiff, fragile or misshapen. These changes impair their ability to transport oxygen. An inability to transport oxygen leads to symptoms such as chronic pain, anemia and organ damage.

It has been found that targeting the DNA region that controls this genetic switch can reactivate fetal hemoglobin production in adults. This breakthrough helps red blood cells function better, eases symptoms and reduces the need for regular transfusions. Ongoing research has now mapped the molecular machinery behind this switch. Thus paving the way for more targeted and effective therapies than ever before.

Rethinking Inherited Blood Disorder Treatments

Until recently, treatments for sickle cell disease and beta-thalassemia relied heavily on blood transfusions, drug therapies and stem cell transplantation. These approaches often come with significant burdens and risks. Recent research has revealed that a segment of DNA near the fetal hemoglobin genetic switch forms a looped three-dimensional structure stabilized by enhancer RNAs. These enhancer RNAs maintain the gene’s “off” position, suppressing fetal hemoglobin production in adults.

Research has highlighted two main strategies, each with its own set of innovations and implications. The first, pioneered by Orkin, applies CRISPR gene editing to directly break the DNA loop and inhibit enhancer RNAs. This effectively reactivates fetal hemoglobin production. This approach, which can be described as ‘breaking the light switch,’ works by altering the DNA sequence itself and has led to the approval of CRISPR-based therapies in the UK.

The second strategy directly targets enhancer RNAs. Rather than changing the DNA. This method collapses the chromatin structure and silences the gene by degrading the enhancer RNAs that maintain the loop. The selective decrease in gene expression in red blood cells restores fetal hemoglobin production and compensates for defective adult hemoglobin. It also spares other tissues where the gene plays important roles. This ‘loosening the wiring’ approach points toward medication-based therapies that could be administered without permanently editing the genome.