Last week, 100,000 Americans with sickle cell disease and millions more around the world got encouraging news. Investors gave a vote of confidence, in the form of a $120 million IPO, to Global Blood Therapeutics (NASDAQ: [[ticker:GBT]]), a four-year-old biotech working on a pill that could become the biggest medical advance ever for the disease.
That pill, which just began its first human trial in January, is a once-a-day medicine that a patient would have to take for life. If approved, the drug would be only the sickle cell treatment to potentially halt the effects of the disease. The lone drug currently on the market for the disease only addresses some of its symptoms.
Patients with sickle cell disease carry a mutated form of hemoglobin that causes normally disk-like red blood cells to change into rigid crescent-shaped cells. Those misshapen cells get hung up in the blood vessels, wreaking all sorts of havoc. In the face of the disease’s worst complications—strokes, deadly lung complications, bouts of excruciating pain, anemia, and more—one pill a day doesn’t seem like much burden. (Global Blood CEO Ted Love declined to answer questions, citing quiet period regulations.)
But even more tantalizing hope lies on the horizon. Gene therapy, ideally a one-shot cure, could arrive in the next decade.
“The first documented sickle cell patient was in 1910, and we only have one medication,” says Sonja Banks, president of the Sickle Cell Disease Association of America in Baltimore, MD. “Anything cutting edge is great; we’re so far behind in the game.”
Banks is fully aware that, as with any new area of medicine, there are still hurdles to overcome in the field of gene therapy, which has seen a renaissance in the past few years. Just recently two gene therapy companies, Celladon (NASDAQ: [[ticker:CLDN]]) and Avalanche Biotechnologies (NASDAQ: [[ticker:AAVL]]), cratered after terrible late clinical results, while others, namely Spark Therapeutics (NASDAQ: [[ticker:ONCE]]) and Bluebird Bio (NASDAQ: [[ticker:BLUE]]), have watched investors flee the stock despite no public setbacks.
And gene therapies for sickle cell, specifically, have a long, long way to go. Bluebird has one in development, called LentiGlobin, and it’s the most advanced. Positive data from a single patient was enough to cause a stir earlier this year, as my colleague Ben Fidler reported.
The therapy requires extracting a sample of the patient’s hematopoietic, or blood-producing, stem cells from the bone marrow, modifying them outside the body, and giving them back to the patient. The technique uses a virus to deliver a healthy copy of the hemoglobin-beta gene into the stem cells. It’s supposed to be a gentler version of bone marrow transplant, which is the only cure so far for the disease.
A bit farther behind Bluebird is a different form of gene therapy, called gene editing, and it should soon provide early milestones in two very different programs. One is based on CRISPR/Cas9, the gene editing system that has spread around the world’s research labs because it’s so easy to use. Three startups—Crispr Therapeutics, Editas Medicine, and Intellia Therapeutics—have raised hundreds of millions of dollars, collectively, to move the system forward into human therapeutics. They have in recent months revealed plans to work on cancer immunotherapy, blood diseases known as hemoglobinopathies (sickle cell is a hemoglobinopathy), and, most recently with Editas, a genetic form of blindness.
But the first data on a CRISPR/Cas9 therapy for sickle cell disease—or any disease, for that matter—to be unveiled could come from a nonprofit effort.
At the Innovative Genomics Initiative, a University of California-funded group on the Berkeley campus, researchers collaborating with Children’s Hospital in nearby Oakland, CA, have been trying to cure sickle cell disease in mice. (IGI was cofounded by Jennifer Doudna, the Berkeley professor who helped turn CRISPR/Cas9, a bacterial defense system, into a gene editing tool. How much she invented is in dispute, as I detailed most recently here.)
IGI scientific director Jacob Corn and colleagues should know in less than two months if their experiments have worked. They’ve removed the hematopoietic stem cells from mice with an approximate version of sickle cell disease, replaced the mutated gene with the healthy version using CRISPR/Cas9, and put the cells back into the mice. Will their blood contain sickled red blood cells? Will the stem cells that repopulate their bone marrow have the sickle mutation? If so, in what numbers?
Corn declines to project what kind of data would move the program closer to a human trial, or to speculate on the timing of a trial , which would take place at Children’s Hospital. But he feels the urgency, not just from doctors and patients but from other academics who are “hot on this trail,” he says.
Taking hematopoietic stem cells out of the body, editing them, and putting them back into the bone marrow to spawn healthy versions of red blood cells is an obvious use of gene editing. “People have wanted to cure sickle cell disease for a long time this way,” says Corn. “It’s a very worthwhile problem, and it’ll be huge when someone cracks the nut. We hope to be the first.” (IGI researchers have used a technical advance that they hope will persuade the edited cells to function properly when reintroduced; Corn declined to reveal the technique until the data are published.)
Gene editing might be a quantum technological leap, but, like Bluebird’s LentiGlobin gene therapy, it would still require a form of bone marrow transplant. When the cells are taken out for editing, the patient’s remaining bone marrow cells would be killed, a precarious procedure that leaves the patient with a compromised immune system for a period of time.
The hope, however, is that both the gene therapy and gene editing approach will lessen the severity and
