CRISPR editing for sickle cell disease

Gray had been exploring the possibility of getting a bone marrow transplant when Frangoul told her about a plan to study gene editing with CRISPR to try to treat sickle cell for the first time. She jumped at the chance to volunteer.

"I was excited," Gray says.

CRISPR enables scientists to edit genes much more easily than ever before. Doctors hope it will give them a powerful new way to fight cancer, AIDS, heart disease and a long list of genetic afflictions.

"CRISPR technology has a lot of potential use in the future," Frangoul says.

To try to treat Gray's sickle cell, doctors started by removing bone marrow cells from her blood last spring.

Next, scientists used CRISPR to edit a gene in the cells to turn on the production of fetal hemoglobin. It's a protein that fetuses make in the womb to get oxygen from their mothers' blood.

"Once a baby is born, a switch will flip on. It's a gene that tells the ... bone marrow cells that produce red cells to stop making fetal hemoglobin," says Frangoul, medical director of pediatric hematology/oncology at HCA Healthcare's TriStar Centennial Medical Center.

The hope is that restoring production of fetal hemoglobin will compensate for the defective adult-hemoglobin sickle cells that patients produce.

"We are trying to introduce enough ... fetal hemoglobin into the red blood cell to make the red blood cell go back to being happy and squishy and not sticky and hard, so it can go deliver oxygen where it's supposed to," Frangoul says.

Then on July 2, after extracting Gray's cells and sending them to a lab to get edited, Frangoul infused more than 2 billion of the edited cells into her body.

"They had the cells in a big syringe. And when it went in, my heart rate shot up real high. And it kind of made it hard to breath," Gray says. "So that was a little scary, tough moment for me."

After that moment passed, Gray says, she cried. But her tears were "happy tears," she adds…

Other doctors and scientists are excited about the research. But they're cautious too.

"This is an exciting moment in medicine," says Laurie Zoloth, a bioethicist at the University of Chicago. "Everyone agrees with that. CRISPR promises the capacity to alter the human genome and to begin to directly address genetic diseases."

Still, Zoloth worries that the latest wave of genetic studies, including the CRISPR sickle cell study, may not have gotten enough scrutiny by objective experts.

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

Zoloth is especially concerned because the research involves African Americans, who have been mistreated in past medical studies.

Frangoul acknowledges that there are risks with experimental treatments. But he says the research is going very slowly with close oversight by the Food and Drug Administration and others…

About two months later, Gray has recovered enough to leave the hospital. She has been living in a nearby apartment for several weeks.

Enough time has passed since Gray received the cells for any concerns about immediate side effects from the cells to have largely passed. And her gene-edited cells have started working well enough for her immune system to have resumed functioning.

So Gray is packing. She will finally go home to see her children in Mississippi for the first time in months. Gray's husband is there to drive her home.

"I'm excited," she says. "I know it's going to be emotional for me. I miss the hugs and the kisses and just everything."…

"So look at this," says Frangoul, smiling, as he hands her a sheet of paper. "This is very exciting. I am super-excited about your results today."

Gray's CRISPR-edited cells seem to be working.

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

Nearly half the hemoglobin in Gray's blood is now fetal hemoglobin, which is more than doctors think is needed to help alleviate the complications of sickle cell. And the level of that protein seems to be continuing to rise.

"Oh my goodness," Gray says.

The treatment also still seems safe, so far. There have been no signs of any ill effects from the modified cells.

In addition, there are clues that the cells could already be helping Gray. She hasn't needed any blood transfusions since she got the cells, hasn't had any pain attacks and hasn't had to rush to the hospital for help.

"That's good. Excellent. Perfect," Frangoul says. "This is extremely encouraging."

Typically, Gray says, she would have had another pain episode by now.

"I would have had at least had something," she says.

"It's special, especially coming up on the holidays — because sometimes I would be in the hospital on Christmas," Gray says. "So I'm looking forward to a whole new life for all of us."…

Zoloth, the University of Chicago bioethicist, says she's encouraged to see progress for a disease that has long been neglected. But she's still cautious about the research, especially because only one patient has been treated, and so recently. She worries about raising false hope.

"So far so good," Zoloth says. "And of course that's great news. I hope it works. I hope she's free of this disease, and I hope this very, very brave woman has a life of joy and freedom from pain and can raise those beautiful children."

But, she adds, "it's still very early days. We're still waiting for 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."

Other doctors are using CRISPR to try to treat cancer. One team soon plans to try to edit genes inside the body for the first time — modifying genes in retinal cells of the eye to try to restore vision to people blinded by a rare genetic disorder.

Gray knows this is just the beginning. But she's happy things are going well so far.

"It's amazing to have a chance at a different type of life," Gray says. "It's a miracle. When you pray and ask God for something for so long, all you have left is hope."

Gray has already started doing things she could never do before, such as go to one of her son's football games for the first time.

"I don't really want anything extravagant," she says. "I just want a simple life with my family and the people who I love and people that love me — and just live, you know?" Gray says. "This could be the beginning of something special."

https://www.npr.org/sections/health-shots/2019/12/25/784395525/a-young-mississippi-womans-journey-through-a-pioneering-gene-editing-experiment

See: https://childnervoussystem.blogspot.com/2019/07/doctors-in-us-use-crispr-tool-to-treat.html
https://childnervoussystem.blogspot.com/2020/03/crispr-editing-for-leber-congenital.html