Sickle Cell Therapy With CRISPR Gene Editing Shows Promise : Shots - Health News NPR tells the exclusive, behind-the-scenes story of the first person with a genetic disorder to be treated in the United States with the revolutionary gene-editing technique CRISPR.

A Young Mississippi Woman's Journey Through A Pioneering Gene-Editing Experiment

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We have a special story for you now on this Christmas Day about a revolutionary gene-editing technique that allows scientists to make precise changes in DNA. They can zero in on any gene, cut out mutations or literally rewrite the genetic code. And for the first time in the U.S., this technology is being used to try to treat someone with a genetic disorder - a woman from Mississippi. NPR health correspondent Rob Stein got exclusive access to chronicle her journey. Now Rob brings us a behind-the-scenes look at this remarkable medical experiment and the woman leading the way.

ROB STEIN, BYLINE: It can always be risky to volunteer for any medical experiment. But Victoria Gray of Forest, Miss., she did something extraordinary. She agreed to have her genes modified for the rest of her life.


STEIN: I met Victoria for the first time this summer at the Sarah Cannon Research Institute in Nashville.

Hello. I'm Rob Stein from NPR.

VICTORIA GRAY: Victoria Gray. Nice to meet y'all.

STEIN: Victoria is sitting up in bed in a hospital gown, wearing a big gold hoop hearings and sparkly eye shadow. She's been here for more than a month. It's just a couple days away from her 34th birthday. She'll be celebrating in the hospital, far away from her husband and four kids.

GRAY: My twins, Jaden (ph) and Jadasia (ph), they are 11. Jamarius (ph) is 12. And my stepdaughter, Asia (ph), is 13.

STEIN: Wow. You've got your hands full (laughter).

GRAY: I do (laughter). It's the right time to get healed.


STEIN: Victoria has been struggling with sickle cell disease all her life.

GRAY: It's horrible. When you can't walk or, you know, lift up a spoon to feed yourself, it gets real hard.

STEIN: Sickle cell is a cruel genetic disorder that afflicts millions of people around the world, including about a 100,000 in the United States. Many are African American.


UNIDENTIFIED HOSPITAL EMPLOYEE #2: Victoria, this one is not going to stop today.

STEIN: A genetic defect turns their red blood cells into deformed sickle-shaped cells. They don't carry oxygen like they're supposed to. They're hard and sticky, so they clog up the bloodstream, wreak havoc in the body. Victoria's mom realized Victoria had sickle cell when she was just 3 months old.

GRAY: My grandma was giving me a bath, and I was crying. So they took me to the emergency room to get me checked out. And that's when they found out that I was having my first crisis.

STEIN: A pain crisis - it's one of the worst things about sickle cell - excruciating, unpredictable attacks of pain.

GRAY: Sometimes it feel like lightning strikes in my chest - and real sharp pains all over. And it's the deep pain. You know, I can't touch it and make it better or do anything to make it better. Sometimes, I will be just balled up and crying, not able to do any day for myself.

STEIN: That sounds just awful.

GRAY: Yes, it is.

STEIN: She often can't get the help she needs when one of those terrible pain attacks hit. One of the things that make sickle cell so hard is doctors refuse to give her enough pain medication. It's not uncommon for doctors to mistake sickle cell patients for people with a drug addiction.


GRAY: You already deal with the pain that you can't do anything about. And then you have to deal with, you know, the hurt of them mistreating you at times. You know? Yeah. So...

STEIN: When she was growing up, Victoria never got to play like other kids. Her sickle cells made her weak, prone to infections. She spent a lot of time in the hospital, recovering, getting blood transfusions - trying to keep up with school.

GRAY: It was hard. You know? Knowing that I wasn't - like, I didn't feel normal - you know, knowing that I couldn't do the regular things that every other kid could do. So I had to kind of be labeled as the sick one, you know?

STEIN: She did graduate from high school on time and went to college to study nursing but had to drop out.

GRAY: That got put on hold for health reasons.

STEIN: Then she got a job selling makeup but had to quit that, too. The sickle cell slowly damaged Victoria's heart and other parts of her body. Victoria knows she's prone to heart attacks, strokes. Many sickle cell patients don't make it past their 40s.

GRAY: It's scary. And it affected my oldest son. He's older, so he understands. So he started acting out at school. And like, his teacher told me, I believe Jamarius is acting out because he really believes you're going to die.

STEIN: I'm so sorry - so sorry.

Some patients can get help from drugs, even try bone marrow transplants. But for most, there's no cure. Victoria's got the most severe form of sickle cell.

GRAY: It was just my religion that kind of kept me going.

STEIN: But then Victoria heard about something new. Doctors were planning to use the gene-editing technique called CRISPR to try to treat sickle cell. Victoria jumped at the chance to volunteer.


HAYDAR FRANGOUL: Hey, Victoria. How are you doing today?

GRAY: I'm doing OK, Dr. Frangoul.

FRANGOUL: That's great.


STEIN: Dr. Haydar Frangoul is starting this study.

FRANGOUL: How was your last night?

GRAY: Last night, it went pretty well.

STEIN: CRISPR lets scientists make very precise changes in DNA much more easily than ever before. They can actually zero in on any part of the genetic code, so doctors think it may give them a powerful new way to fight cancer, heart disease, even AIDS.

FRANGOUL: CRISPR technology has a lot of potential use in the future, not only in blood disorders, in other genetic disorders to help many other patients.

STEIN: Now here's how CRISPR might help sickle cell patients like Victoria. Sickle cell is caused by a defective protein called hemoglobin. It's what red blood cells need to carry oxygen around the body. So when it's defective, red blood cells don't work. They jam up the bloodstream.


STEIN: Frangoul hopes to solve this problem using something called fetal hemoglobin. It's what fetuses use to get oxygen when they're in the womb.

FRANGOUL: Once a baby is born, a switch will flip on. It's a gene that tells the red blood cell - the bone marrow cells that produce red cells - to stop fetal hemoglobin.

STEIN: So Frangoul is using cells that scientists edit with CRISPR to flip that fetal hemoglobin switch to turn the production of healthy fetal hemoglobin back on.

FRANGOUL: What we are trying to do here is we are trying to introduce enough fetal hemoglobin into the red blood cell to make the red blood cell go back to being happy, squishy and not sticky and hard - and can go deliver oxygen where it's supposed to.

STEIN: So first, Frangoul gets some of Victoria's bone marrow cells. Next, he sends them off to a lab, where scientists edit a gene in the cells. Then, Victoria gets a grueling round of chemotherapy to make room in her bone marrow for the edited cells.

FRANGOUL: Let's go for it.

STEIN: Finally, Dr. Frangoul infuses more than 2 billion of those genetically modified cells into her body. The hospital recorded the procedure. A nurse hands Dr. Frangoul a big syringe filled with the edited cells.

FRANGOUL: OK. Perfect.

STEIN: He pushes the plunger.

FRANGOUL: All right - almost done.

GRAY: Yeah.

When it went in, my heart rate shot up real high and kind of made it hard to breathe. So that was a little scary, tough moment for me. After that, I cried. But it was happy tears - you know, just kind of overwhelming after all that I had went through to finally get what I came for (laughter).

STEIN: Now, these cells won't cure sickle cell. But the hope is they'll prevent the terrible complications of the disease.

FRANGOUL: And this opens the door for many patients to potentially be treated and have their disease modified to become mild or cause them no long-term side effects from the horrible, horrible side effects of sickle cell disease.

STEIN: Victoria calls her new gene-edited cells her...

GRAY: Supercells - yeah, they got to be super to do great things in my body - you know? - and to help me be better - you know? - and help me have more time with my kids and my family.


STEIN: Other doctors and scientists are excited about studies like this, too. But they're also being cautious. Whenever you try anything so new, it's always risky. Laurie Zoloth is a bioethicist at the University of Chicago.

LAURIE ZOLOTH: This is an exciting moment in medicine. Everyone agrees with that. CRISPR promises the capacity to alter the human genome and to begin to directly address genetic diseases. But no one knows.

STEIN: She worries that this sickle cell study may not have gotten enough scrutiny by objective experts.

ZOLOTH: This is a brand-new technology. It seems to work really well in animals and really well in culture dishes. It's completely unknown how it works in actual human beings. So there are a lot of unknowns. It might make you sicker.

STEIN: Dr. Frangoul knows there are always risks with experimental treatments. But he says the research is going very slowly with a lot of oversight by the Food and Drug Administration and others.

FRANGOUL: We are very cautious about how we do this trial in a very systematic way to monitor the patients carefully for any complications related to the therapy.

STEIN: Victoria says she understands she's taking a chance by being the first patient and that the study may only help other patients years from now. Still, she can't help but hope.

GRAY: Being able to wake up and not be in pain and to just be tired because I've done something - and not just tired for no reason - just be outside and jump on the trampoline with my kids and go to graduations and weddings and see them grow up. That means the world to me.

STEIN: Dr. Frangoul will keep a close watch over Victoria to see what the gene-edited cells are doing in her body, so Victoria will stay in Nashville for weeks, maybe months to recover and get strong enough to go home.

FRANGOUL: So how have you been doing?

GRAY: I'm doing good.

FRANGOUL: This is a big moment, friend.

GRAY: Yes.

STEIN: It's two months later. Victoria's still in Nashville. She's been living in an apartment near the hospital, but her new genetically modified cells have started working well enough to let her leave. She's finally going home to her family in Forest, Miss.

FRANGOUL: Excited about seeing the kids?

GRAY: Yes, I am.

FRANGOUL: Are they going to have a big welcome sign for you in Mississippi?

GRAY: No - because it's a surprise. No one knows I'm coming.

FRANGOUL: Oh, you did not tell them?


FRANGOUL: Oh, wow. So they don't know you are coming?

GRAY: No, no, no. I'm just going to show up tomorrow, like, Mama's home (laughter).

FRANGOUL: That's pretty good. OK. Let's check you out.


FRANGOUL: Take a deep breath for me.

GRAY: (Exhaling).

FRANGOUL: Deep breath.

GRAY: (Exhaling).


STEIN: Before she leaves the hospital, the nurses need to draw some of Victoria's blood.

UNIDENTIFIED HOSPITAL EMPLOYEE #3: Ninety-seven-point-nine.

STEIN: This is a crucial part of the study. It's being run by two biotech companies and will eventually involve dozens of patients in the United States, Canada and Europe.

UNIDENTIFIED HOSPITAL EMPLOYEE #3: All right. So how many days have you been here?

GRAY: I think we're in, like, day 80.

UNIDENTIFIED HOSPITAL EMPLOYEE #3: Aw, I can't believe you're really leaving.

STEIN: As the nurses fill one big vial after another, I realize I never asked Victoria something.

Is it weird to have genetically modified cells in your body?

GRAY: No, I'm just genetically modified now (laughter). I'm a GMO. Is that what they call it? (Laughter).

STEIN: Finally, the nurses are done. It's time to say goodbye - for now.


GRAY: Thank y'all. Y'all going to make me cry.


STEIN: Victoria will keep detailed diaries about her health when she gets home to Mississippi. Dr. Frangoul wants to know how much pain she's having, how much pain medication she takes - will she need blood transfusions?

FRANGOUL: We are very hopeful that this will work for Victoria, but we don't know that yet.

STEIN: So every month, Victoria will drive more than five hours back to Nashville to get her blood tested to find out if the edited cells are making enough fetal hemoglobin to make her better.

FRANGOUL: Victoria is a pioneer in this. And we are very excited. This is a big moment for Victoria and for this pivotal trial because if we can show that this therapy is safe and effective, it can potentially change the lives of many patients.

STEIN: Victoria hopes so, too.

GRAY: Not just for me but for other people - this would be mind-blowing. And - oh, my God - I can't imagine, you know, the lives that could be saved if this thing actually works.

STEIN: Victoria starts packing. Her husband is there to bring her home.

GRAY: I'm excited, you know? I'm very excited about it. I know it's going to be emotional for me. I miss the hugs and the kisses and just everything.

STEIN: She opens the closet door and starts laughing.

GRAY: Oh, my goodness. Did I really bring all of this? That's one.

STEIN: First suitcase done?

GRAY: Yes (laughter).

STEIN: Victoria is now heading into a period of limbo, waiting to find out if her gene-edited cells are starting to work. I asked her how she feels about that.

GRAY: Well, I'm spiritual, Rob. And it's something I prayed about. And just the way everything happened for me, I just feel like it was fate for me to be here. So I just believe that, you know, God is doing this for me. That's all I can say. So (laughter) - yes, pray.

STEIN: It's a foggy morning about a month later. I'm waiting in a parking garage in downtown Nashville.

GRAY: It's been a while.

STEIN: Yeah, it's been a while.

Victoria has just driven back from Mississippi for her first check-in.

So this is an exciting day for you, huh?

GRAY: Yes, it is.

STEIN: How are you feeling?

GRAY: I feel good. I'm hoping to get some good news today.

STEIN: From her doctor - she'll be getting the results of her latest blood tests.

Are you nervous at all?

GRAY: No, I'm not. No.


GRAY: Uh-uh - just about the needles (laughter).

STEIN: Victoria will have to get a ton more blood drawn today.


GRAY: Yes, Victoria Gray for Dr. Frangoul.

UNIDENTIFIED HOSPITAL EMPLOYEE #5: Could you go ahead and sign in for me?


STEIN: Victoria's wearing a black sweatshirt with big letters spelling out warrior.

I like your sweatshirt.

GRAY: Thank you. Yeah. You know, they call sickle cell patient warriors. And I saw this shirt at Walmart, so I had to get it (laughter).

STEIN: Oh, I did not know they called sickle cell patients warriors.

GRAY: Yes. Because it's a constant battle, you have to be to deal with it.

UNIDENTIFIED HOSPITAL EMPLOYEE #6: You can go on back now.

STEIN: Victoria finds an empty chair, sits down and stretches out her arm for the nurses.

UNIDENTIFIED NURSE: All right. So you're going to feel a stick on three. OK? One, two, three - stick. All right. So you should be good.

STEIN: As the nurses fill one big tube after another, I ask Victoria about her homecoming a few weeks earlier, when she got to see her four kids for the first time since she spent the summer in Nashville getting her genetically modified cells.

GRAY: My oldest son, when he did his double take and realized I was in the car, he took off running. And he just grabbed me and held onto me. Yeah. And the twins saw me from the inside the house. They knew it was Mama. This is emotional for me, you know, 'cause I love them so much. I did this for them. Yeah. So it's worth it.

UNIDENTIFIED NURSE: OK. All finished. You did great.

GRAY: Thank you.

STEIN: Victoria heads over to see her doctor.

FRANGOUL: How are you? How are you? You're doing all right?

STEIN: Dr. Haydar Frangoul.

FRANGOUL: OK, great. Let's check you out. Take a deep breath for me.

GRAY: (Exhaling).

FRANGOUL: Deep breath.

GRAY: (Exhaling).

FRANGOUL: Good job. Well, you look amazing, Victoria. You look really good.

STEIN: After the exam, Dr. Frangoul shows Victoria what she's been waiting for - the results of some of her blood tests.

FRANGOUL: So look at this. This is very exciting. Are you excited about it?

GRAY: Yes, I am.

FRANGOUL: OK. I am super excited about your results today.

STEIN: That's because, so far, it seems to be working. Victoria's genetically modified cells have started doing what they're supposed to be doing.

FRANGOUL: It looks like there are signs that you are starting to make fetal hemoglobin, which is very exciting for us.

STEIN: So far, nearly half the hemoglobin in her blood is fetal hemoglobin, that protein Dr. Frangoul hopes will help Victoria. And it looks like it's still rising.

GRAY: Oh, my goodness.

FRANGOUL: So I'm very, very proud of you. You are doing really well. Everything looks wonderful. OK?


STEIN: The treatment seems safe so far, and there are clues that the edited cells may already be helping Victoria. She hasn't needed any blood transfusions since she got the cells, hasn't had any of those awful attacks of pain.

FRANGOUL: And you haven't been in the hospital since I last saw you, correct?

GRAY: No, it's...

FRANGOUL: That's good. Excellent. Perfect.

STEIN: And so is that because of the procedure - because of the cells?

FRANGOUL: Well, we are hoping it is. Again, it is too early to figure it out. But this is extremely encouraging. We are very happy that she didn't have any ER visits. She hasn't had any hospital stays since we've done the procedure. So this is really good.

STEIN: And is that unusual? Would you have expected to usually have a pain episode in this period?

GRAY: Of course. Like, with the time that passed by, I would at least have had something. You know?

STEIN: Wow. That sounds amazing.

GRAY: Yeah, it is for me. It's special, especially coming up on the holidays 'cause sometimes I would be in the hospital on Christmas. And so I'm looking forward to a whole new life for all of us.

STEIN: The same kind of CRISPR-edited cells also seem to be helping a patient in Germany who got them for a similar genetic blood disorder called beta thalassemia. But Dr. Frangoul knows he has to be cautious.

FRANGOUL: It is still too early to celebrate. I just want to make sure this is something we watch very carefully every visit and see how things are going.

STEIN: Doctors will have to follow Victoria for years and study many more patients to answer the big questions. Are the cells really helping patients live healthier lives? Will they keep working? Will they keep working safely? And will they actually help patients live longer?

FRANGOUL: This would be life-changing, not only for Victoria but for many sickle cell patients - because if this is determined to be safe and effective, I think it can be transformative for patients with sickle cell disease.

STEIN: That seems life-changing for her, really.

FRANGOUL: Yes, it definitely does - although it is too early to celebrate. So we are observing her very carefully to see how she does.

STEIN: Other kinds of genetic therapies are also showing promise for sickle cell, a disease long neglected by medical science. The problem is they're all complicated and expensive. Will they be practical and affordable - here and especially in poor countries where these diseases are most common? Francis Collins heads the National Institutes of Health.

FRANCIS COLLINS: The progress that we've seen for sickle cell disease, including Victoria Gray and her involvement in this, made it clear that if this is starting to work, we need to get busy and figure out how to take it to the next level. To be able to take this new technology and give people a chance for a new life is a dream come true for those who've waited a long time. And here we are.

STEIN: And Laurie Zoloth, the University of Chicago bioethicist, she still worries, especially when it's just one patient who was only treated a few months ago - and especially when it involves African Americans, who've been mistreated by medical studies in the past. She worries about creating false hope.

ZOLOTH: So far, so good. And of course, that's great news. I hope it works. I hope she's free of this disease. And I hope this very brave woman has a life of joy and freedom from pain and can raise those beautiful children. But it's still very early days. We're still waiting for the real news, which is this is the definitive cure; this will help many, many thousands of people. It would be a wonderful thing for humanity.

STEIN: Other doctors already are trying to use CRISPR to treat cancer. And for the first time, a team is planning to edit genes with CRISPR while they're still inside the body. They hope to restore vision to people blinded by a rare genetic disorder.


STEIN: As for Victoria, she says she knows this is just the beginning. But she's happy it's going well so far.

So your supercells seem to be working.

GRAY: Yeah, they seem to be super after all, huh? (Laughter). Yes.

STEIN: Victoria is already doing things she never did before. Like, she got to go to one of her son's football games for the very first time.

GRAY: You know, the simple things in life - I don't really want anything extravagant. I just want a simple life with my family - you know, people that I love and people that love me - and just live. You know?


GRAY: This could be the beginning of something special (laughter).


SHAPIRO: This story was reported by NPR health correspondent Rob Stein, produced by Jane Greenhalgh with help from Maria Paz Gutierrez and edited by Joe Neal (ph). We'll continue to follow Victoria Gray's journey.

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