REWRITING THE RULES OF SICKLE CELL TREATMENT

Stanford chemical biologist Laura Dassama is on a personal mission to design a simpler, more affordable sickle cell therapy

By the time Laura Dassama, PhD, was 5, she had already met the disease that would help define her future. The pain was unpredictable and searing, sometimes flaring in her limbs, sometimes in her chest. Sickle cell disease, a hereditary blood disorder, was something she and her sister would learn to navigate together while growing up in Liberia.

Today, as an assistant professor of microbiology and immunology and of chemistry at Stanford University, Dassama is confronting sickle cell disease from a new vantage point: the laboratory.

“I’ve seen it firsthand. I’ve lived with it,” she said. “And I know that, for many people, the current treatments just aren’t enough. We need more options, and we need therapies that are both effective and accessible.”

Sickle cell disease stems from a single mutation in the gene responsible for helping make hemoglobin, the oxygen-carrying protein inside red blood cells. The resulting faulty version of hemoglobin tends to clump, distorting normally round red cells into stiff, crescent-shaped “sickles.” These misshapen cells can clog blood vessels and break down easily, leading to chronic anemia, pain and organ damage.

Doctors have long known that one way to counteract sickle cell disease is to induce the body’s production of a fetal version of hemoglobin, which binds more tightly than the adult form, ensuring that developing fetuses can claim some of the oxygen circulating through their mom’s body.

Shortly after they’re born, babies’ bodies switch to making adult hemoglobin and, for most people, production of fetal hemoglobin stops altogether. But some people keep small amounts into adulthood — and studies have found that people with sickle cell disease who retain some fetal hemoglobin tend to fare far better. 

Red blood cells with higher levels of fetal hemoglobin are more resistant to clumping and sickling — even when the sickle cell mutation is still present. “If we could reliably boost fetal hemoglobin levels, we could dramatically reduce symptoms for many people,” Dassama explained.

For decades, researchers have dreamed of turning the production of fetal hemoglobin back on in adults with sickle cell disease. One drug, hydroxyurea, does so in some patients, though no one’s sure why it works — and it doesn’t work for everyone. 

More recently, gene-editing therapies have been shown to disable the genetic switch that normally shuts fetal hemoglobin production down, allowing it to turn back on. 

But these therapies are complex, expensive procedures that require harvesting, editing and re-implanting a patient’s own bone marrow cells. “It can take over a year,” Dassama said. “And the cells don’t always survive the process.”

Reawakening healthy hemoglobin

Dassama’s lab is exploring a simpler, cheaper and faster way to switch on fetal hemoglobin production. Her team is targeting a protein called BCL11A, which acts as the genetic off switch to prevent most adults’ bodies from making the fetal hemoglobin. Her lab has designed a molecule that tags BCL11A for destruction by the cell’s own waste-disposal system. Her new molecule acts like a “get rid of me” flag for BCL11A, and once BCL11A is cleared away, fetal hemoglobin can reemerge.

“It’s a different kind of precision medicine,” Dassama said. “We’re not rewriting the genome — we’re guiding the cell to do something it already knows how to do.”

While still in early stages, the approach reflects a growing interest in finding druglike molecules that can eliminate disease-driving proteins, especially those long considered “undruggable.” BCL11A is one of them — its structure doesn’t have the usual nooks and crannies that drugs can recognize. But Dassama’s background in chemical biology gives her a unique tool kit.

Her lab has already identified a molecule that binds BCL11A, and they’ve added the flag that sends it to the cellular trash bin. The next step: ensuring the drug can effectively get into blood cells to do its job. Dassama said she hopes the strategies developed in this project will apply to other so-called undruggable targets.

But Dassama’s motivation goes beyond the science. She’s acutely aware of the need for treatments that are not only effective but also accessible — especially in parts of the world where sickle cell is most common, including sub-Saharan Africa.

“This disease affects millions of people, but too often they don’t have access to cutting-edge therapies,” she said. “My goal is a treatment that you don’t need a specialty clinic or a million-dollar lab to receive. Something people could access.

Related content: In a new episode of Stanford Medicine’s Health Compass podcast, Laura Dassama, PhD, describes her work to develop new kinds of therapies for sickle cell patients.

This article was originally published in Stanford Medicine Magazine on Monday, September 22nd.