Gene Therapy Advances Offer Hope For Sickle-Cell Disease Cure

With Meghna Chakrabarti

Sickle-cell disease is a painful, debilitating and potentially fatal disease that affects more than 100,000 Americans. It's caused by a mutation in a single gene and for decades a sickle-cell disease diagnosis meant certain suffering for patients who are mostly of African descent.

But now, advances in gene therapy have come far enough that some scientists are daring to wonder if a cure may be on the horizon.

Dr. David Williams, president of the Dana-Farber and Boston Children’s Cancer and Blood Disorders Center. Chief scientific officer and senior vice president of Boston Children's Hospital and a professor at Harvard Medical School.

Manny Johnson, first patient to receive an experimental therapy aimed at curing his sickle-cell disease, which he was diagnosed with at birth.

On life with sickle-cell disease, and the transformative results of the gene therapy

Manny Johnson: "It is rather difficult. You know, everybody shares it differently. Pain crisis, I can't walk very far. Pain in the joints. Migraines, very frequently. Unable to do a lot of physical activity.

"Everything [has changed]. I feel reformed. You know, I don't have the same bodily damage, I guess is what I would call it. I feel natural. I don't have to go to the hospital anymore — or at least not as often."

On the significance of living symptom-free thanks to the therapy

Dr. David Williams: "I think it's a sign that the all the basic research that we've been doing for a number of years has, it looks like, successfully been translated into a very effective therapy. So Manny has been on once-a-month red blood cell transfusion since around the age of 4, when he had actually had a stroke, which is common in children with sickle-cell disease. So for him, he's no longer requiring blood transfusions at all. And as he said to you, he's no longer having symptoms of sickle-cell disease. So, for me, what's remarkable is 30 years ago, when I first started my training in sickle-cell disease to now, we've basically not changed very much what we do for patients with sickle-cell disease. We still treat their pain crisis with heavy pain medicines. Some patients like Manny go on blood transfusions, which has its own problems and risk. And we do use a drug called Hydroxyurea. The purpose of that drug is to elevate the fetal hemoglobin in sickle-cell patients' blood, and that's effective in some patients but not all patients. So, it's a remarkable — for those of us in the field — it's a remarkable opportunity we think to really make a difference and in some patients' lives with sickle-cell disease."

"Doctors always hate to use the word 'cure,' because it suggests that we we can predict the future, which we can't. But we're optimistic that this is really going to be beneficial in the long term for patients."

Dr. David Williams

On the nature of the disease

Dr. Williams: "There's two major parts of the disease. One is the red cells are misshapen and therefore they don't live long enough in the bloodstream, they don't live as long as a normal red cell. And that causes those cells to be constantly broken down, and the person is almost always anemic. And then the second part that's even more debilitating, for most patients, is those misshapen cells occlude the small blood vessels that give oxygen to all your vital organs. And so if you can think about a person essentially having a heart attack, patients with sickle-cell disease have that kind of pain throughout their body. And it's called vaso-occlusion, and that, over time, of course, creates chronic damage to those organs from a lack of oxygen and that leads to lots of chronic problems in organs such as the kidneys, the eyes, the bones, in particular, the lungs. These are the debilitating parts of the disease over a long period of time that we're trying to develop a way to prevent these chronic complications."

On what exactly the gene therapy is doing in patients' bodies

Dr. Williams: "When you're a baby in your mother's womb, your body knows to make a certain kind of hemoglobin molecule called fetal hemoglobin. And when you're born, the body knows to quit making that form of hemoglobin and start making adult form hemoglobin, called adult hemoglobin. And the reason that that's so critical for sickle-cell patients is that the mutation and causing the disease is on the adult globin gene, not on the fetal globin gene. And so basic research has gone over, now, for 40 years, has tried to understand what we call that switch, a switch from fetal to adult hemoglobin. And researchers here at Children's — Vijay Sankaran and Stu Orkin — discovered several years ago the basis of that, and what we've done for the gene therapy trial is develop a virus that instructs the cells to flip the switch back to a fetal globin. That simultaneously gets rid of or reduces a large portion of the sickle globin that causes the problem. And, at the same time, the fetal hemoglobin is quite protective to the sickle-ing process. It's a rheostat that works in the favor of the patient both ways, increasing the fetal hemoglobin and reducing the sickle hemoglobin."

On discussion of a "cure"

Dr. Williams: "Well, I think we are close to that. In the gene therapy field, we have now a number of rare gene mutation diseases where it looks like this approach of gene therapy actually permanently corrects the individuals' symptomology. Manny is now seven, eight months since his infusions, so that's still pretty early. The way we're doing it would be predicted to be long term. And at the level that Manny has had a resolution of symptoms, I think he would agree, it feels like a cure to him. We always, as you can imagine, doctors always hate to use the word 'cure,' because it suggests that we we can predict the future, which we can't. But we're optimistic that this is really going to be beneficial in the long term for patients like Manny."

Dana-Farber Cancer Institute: "New gene therapy strategy for sickle cell disease shows early promise in humans" — "Dana-Farber/Boston Children's Cancer and Blood Disorders Center reports positive results treating sickle cell disease in its first patient, using a novel gene therapy approach that induces production of fetal hemoglobin while silencing production of the abnormal sickle form of adult hemoglobin. The research team, led by David A. Williams, MD, will share findings in the trial’s first patient on Saturday, Dec. 1 at the 60th Annual American Society of Hematology (ASH) meeting in San Diego, Calif.

"In sickle cell disease, a mutation in the hemoglobin molecule, which carries oxygen, distorts red blood cells into a crescent or sickle shape. This can block red blood cells from passing through blood vessels and delivering oxygen to organs and tissues. Symptoms include anemia, repeated pain episodes that often require hospitalization and life-threatening organ damage.

"The investigator-initiated clinical trial used a form of gene therapy designed to knock down the expression of the BCL11A gene to allow production of high levels of fetal hemoglobin. The first patient, a 21-year-old male who previously required monthly blood transfusions, is symptom-free, has significantly increased levels of fetal hemoglobin and has no demonstrable sickled cells in his blood. Researchers now plan to treat additional patients between ages 3 and 40 in the ongoing clinical trial."

New York Times: "These Patients Had Sickle-Cell Disease. Experimental Therapies Might Have Cured Them." — "Scientists have long known what causes sickle-cell disease and its devastating effects: a single mutation in one errant gene. But for decades, there has been only modest progress against an inherited condition that mainly afflicts people of African descent.

"With advances in gene therapy, that is quickly changing — so much so that scientists have begun to talk of a cure.

"In a half-dozen clinical trials planned or underway, researchers are testing strategies for correcting the problem at the genetic level. Already a handful of the enrolled patients, who have endured an illness that causes excruciating bouts of pain, strokes and early death, no longer show signs of the disease.

"Among them is Brandon Williams, 21, who lives with his mother in Chicago. Because of his sickle-cell disease, he had suffered four strokes by age 18. The damage makes it hard for him to speak. His older sister died of the disease."

Anna Bauman produced this segment for broadcast. Alex Schroeder adapted this interview for the web.