When it’s time for St. Jude Children’s Research Hospital patients with sickle cell disease to transition to adult care, Mitchell Weiss, MD, PhD, relishes the moment when he shakes each one’s hand during a heart-warming sendoff. But Weiss, chair of St. Jude Hematology, says he and his department colleagues would like to tweak that ceremony just a bit and send them off cured.
The key to realizing that goal may lie in “tweaking” patients’ DNA. In the lab, St. Jude scientists have shown that a gene-editing technique called CRISPR may prompt sickle cell patients’ misshapen and dysfunctional red blood cells to become healthier. Ordinarily, these sickle-shaped cells clog circulation, causing severe pain, recurrent strokes and organ damage.
The new, proof-of-principle research adds CRISPR gene editing to an expanding list of gene therapies pioneered at St. Jude to ease the devastating effects of sickle cell disease. The life-threatening inherited disorder affects about 100,000 Americans, including 900 being treated at St. Jude.
“These kids suffer a lot. There are treatments, but none are optimal, and cures are possible but hard to come by,” Weiss explains. “It’s frustrating to feel like you’re doing the best you can, but it’s not enough. It would really feel good to be able to do something to fix this terrible disease.”
Longtime gene therapy leader
St. Jude has long been at the forefront of gene therapy efforts, which date back to the 1980s when hematologist Arthur Nienhuis, MD, became the hospital’s CEO. A pioneer in the field of gene therapy, Nienhuis paved the way for advances in the field. The hospital now offers promising therapies for patients with certain forms of hemophilia and severe combined immunodeficiency disease using viral vectors that replace the defective gene product.
Weiss says the CRISPR gene-editing technique may ultimately work better in sickle cell and related blood disorders such as beta-thalassemia because it modifies the patient’s own DNA to correct the disease. In patients’ blood-forming stem cells, scientists use a tool to snip the DNA at a specific location to mimic mutations found in a genetic condition called hereditary persistence of fetal hemoglobin (HPFH).
In this harmless, naturally occurring condition, patients’ levels of fetal hemoglobin are elevated, making them resist sickle cell symptoms. Fetal and adult hemoglobin are two different forms of the essential oxygen-carrying molecule in red blood cells, and adult hemoglobin typically takes hold after birth. By editing genes in sickle cell or beta-thalassemia patients, scientists can reverse this “switching” process, which enables fetal hemoglobin’s benefits to persist, thus curing the patient.
“If you recreate the HPFH mutation, you can inhibit the switching and keep fetal hemoglobin levels high, alleviating symptoms of the disease, even though the patient still carries the mutation,” Weiss says. “Right now, for technical reasons, it’s easier to use CRISPR to destroy a gene or genetically control an element in blood-forming cells than it is to change a mutated gene into a normal one.”
Safety is the priority
The St. Jude gene-editing work is especially valuable because sickle cell patients often face recurring pain, organ damage and early death despite improved therapies. The only potential cure, a bone marrow transplant, comes with major risks, including donor cell rejection, infertility from chemotherapy, or death from complications.
While CRISPR is currently considered the simplest, most precise method of gene editing, the technique is several years away from being used in patients. First, scientists don’t yet know how many cells need to be altered to result in enduring health benefits. Perhaps more importantly, researchers also need to determine if gene editing might create other, “off-target” mutations that might sicken patients.
“You could create mutations that aren’t the ones you want,” Weiss says. “You have to make sure you’re not going to cause the patient a problem.”
High hopes for ‘amazing technology’
CRISPR gene editing in sickle cell research manages to avoid the controversy elsewhere surrounding the technique’s proposed use to edit germline or reproductive cells—changes that could be passed from generation to generation. In sickle cell disease and other blood disorders, only patients’ somatic, or non-reproductive, cells are altered.
Weiss and his colleagues, including student Elizabeth Traxler of St. Jude Hematology, recently published an article on their research in the journal Nature Medicine. Weiss enthusiastically embraces gene editing for its ease in the lab, but cautions that its clinical benefits must still be proven.
“It’s an amazing technology. It’s changing the way we work in the lab,” he says. “It’s always fun to have an experiment work and even more fun when down the road the result might have a clinical application.”
“Nature has dealt sickle cell patients a bad hand,” Weiss continues. “If they could leave here cured, we would all feel good.”
From Promise, Winter 2017