Gene therapies for sickle cell disease come with hope and challenges

Pediatrician Erica Esrick discusses existing sickle cell treatments and an ongoing clinical trial

Today, it’s clear that our genes not only cause many diseases, but also hold potential cures. But that wasn’t always the case. It wasn’t until 1949 that scientists first found the molecular culprit of a disease — its roots in the genetic code. The disease was the blood disorder known as sickle cell disease, an inherited disorder that causes severe and debilitating pain. Now, nearly 75 years later, researchers are developing gene therapies to cure it.

Sickle cell disease results from a change in a key protein in hemoglobin, which helps transport oxygen in red blood cells. Hemoglobin normally allows “red blood cells to be very floppy and pliable, and slip and slide through the blood vessels easily,” says pediatrician Erica Esrick. But a mutation in a single gene, the HBB gene, makes hemoglobin stack in long strings inside blood cells, giving them an inflexible, sickle shape. Instead of being “squishy,” the stiff red blood cells get stuck inside blood vessels, blocking blood flow.

Sickle cell affects millions of people around the world, particularly those whose ancestors come from sub-Saharan Africa, parts of the Middle East and Southeast Asia. In the United States, for instance, approximately 100,000 people live with the disease, most of them Black or Latino. People with sickle cell disease have a shortened life expectancy, living only into their late 40s on average, in large part due to strokes or organ damage from blocked blood vessels. Esrick, of Boston Children’s Hospital and Harvard Medical School, and others are trying to fight the disease through gene therapy.

Gene therapies seek to manipulate the very information of life by replacing, inactivating or fixing missing or broken genes — and so curing patients. But the journey to today’s handful of approved gene therapies, including for diseases like severe combined immunodeficiency syndrome, or SCID, certain blood cancers and spinal muscular atrophy, has been rocky. Early clinical trials in the 1990s weren’t effective, and the 2000s brought unintended and sometimes deadly consequences, including a leukemia-like illness.

Despite gene therapy’s challenges, many researchers believe sickle cell is a good target because the molecular pathways are well understood and straightforward. What’s more, every copy of the gene doesn’t need to be mended to have an effect. (Individuals who inherit the mutated gene from only one parent, for example, don’t develop sickle cell disease.)

Esrick is co-leading a clinical trial testing a gene therapy that attempts to encourage the body to make more of a healthy type of hemoglobin produced by fetuses and young babies — but not adults — called fetal hemoglobin. DNA for making a short string of genetic material called a microRNA is delivered by a virus into cells from a patient’s bone marrow. The virus, called a vector, permanently inserts the DNA into the cell’s genetic blueprint. The microRNA then interferes with the production of a protein that prevents fetal hemoglobin from being made. Once that protein is blocked, fetal hemoglobin production turns back on. Like turning on a faucet, a steady stream of the healthy hemoglobin can flow into the bloodstream, making up for the faulty form.

Preliminary data released in January 2021 showed that the treatment helped six sickle cell patients make fetal hemoglobin, Esrick and colleagues reported in the New England Journal of Medicine. During the follow-up period, ranging from several months to more than two years, the patients’ symptoms were reduced or eliminated. The team has expanded the trial to include more patients and further test the treatment.

Scientists are testing other ways to tackle sickle cell via gene therapy, too. A biotechnology company called bluebird bio is testing an approach that delivers a functional copy of the HBB gene to patients. Another team is preparing to begin a trial that will edit that gene directly using CRISPR/Cas9.


Leave a Reply

Your email address will not be published. Required fields are marked *