Victoria Gray (right), shown with researcher Haydar Frangoul, was the first patient to be treated with the gene-editing tool CRISPR for sickle cell disease.

By Jocelyn KaiserDec. 5, 2020 , 12:30 PM

It is a double milestone: new evidence that cures are possible for many people born with sickle cell disease and another serious blood disorder, beta-thalassemia, and a first for the genome editor CRISPR.

In todays issue of The New England Journal of Medicine (NEJM) and tomorrow at the American Society of Hematology (ASH) meeting, teams report that two strategies for directly fixing malfunctioning blood cells have dramatically improved the health of a handful of people with these genetic diseases. One relies on CRISPR, marking the first inherited disease treated with the powerful tool created just 8 years ago. And both treatments are among a wave of genetic strategies poised to widely expand who can be freed of the two conditions. The only current cure, a bone marrow transplant, is risky, and appropriately matched donors are often scarce.

The novel genetic treatments still need longer folllow up, have the same safety issues as bone marrow transplants for now, and may also be extraordinarily expensive, but there is hope those risks can be eliminated and the costs pared down. This is an amazing time, and its exciting because its happening all at once, says hematologist Alexis Thompson of Northwestern University, who with a company called Bluebird Bio continues to test yet another genetic strategy that first demonstrated a sickle cell fix several years ago.

People born with sickle cell disease have mutations in their two copies of a gene for hemoglobin, the oxygen-carrying protein in red blood cells. The altered proteins stiffen normally flexible red blood cells into a sicklelike shape. The cells can clog blood vessels, triggering severe pain and raising the risk of organ damage and strokes. Sickle cell disease is among the most common inherited diseases, affecting 100,000 Black people in the United States alone. (The sickling mutations became widespread in African people, as one copy protects blood cells from malaria parasites.)

People with beta-thalassemia make little or no functioning hemoglobin, because of other mutations that affect the same subunit of the protein. About 60,000 babies are born each year globally with symptoms of the disease, largely of Mediterranean, Middle Eastern, and South Asian ancestry. Blood transfusions are standard treatment for both diseases, relieving the severe anemia they can cause, and drugs can somewhat reduce the debilitating crises that often send sickle cell patients to the hospital.

In the two new treatments, investigators have tinkered with genes to counter the malfunctioning hemoglobin. They remove a patients blood stem cells and, in the lab, disable a genetic switch called BCL11A that, early in life, shuts off the gene for a fetal form of hemoglobin. The patient then receives chemotherapy to wipe out their diseased cells, and the altered stem cells are infused. With the fetal gene now active, the fetal proteinrestores missing hemoglobin in thalassemia.In sickle cell disease it replaces some of the flawed adult sickling hemoglobin, and also blocks any remaining from forming sticky polymers.

Its enough to dilute the effect, says Samarth Kulkarni, CEO of CRISPR Therapeutics, which partnered with Vertex Pharmaceuticals on using the genome editor.

They engineered CRISPRs DNA-cutting enzyme and guide RNA to home in on and break the BCL11A gene. In a more traditional gene therapy effort, a team led by gene therapy researcher David Williams of Boston Childrens Hospital achieved the same goal. They used a harmless virus to paste into the blood stem cells genome a stretch of DNA coding for a strand of RNA that silences the fetal hemoglobin off switch.

Patients treated in both trials have begun to make sufficiently high levels of fetal hemoglobin and no longer have sickle cell crises or, in all but a single case, a need for transfusions. In one NEJM paper today, the Boston Childrens team reports on the success of its virus gene therapy in six sickle cell patients treated for at least 6 months. They include a teenager who can now go swimming without pain, and a young man who once needed transfusions but has gone without them nearly 2.5 years, says Erica Esrick of Boston Childrens. He feels perfectly normal.

CRISPR appears to have done at least as well. The first sickle cell patient to receive CRISPR 17 months ago, a Mississippi mother of four named Victoria Gray, has called the results wonderful. We have amelioratedthe symptoms, says Haydar Frangoul, a hematologist at the Sarah Cannon Research Institute who treated Gray as part of the CRISPR trial. Every time I call her on the phone or see her in the clinic, she feels great.

CRISPR Therapeutics and Vertex describe the results for Gray and one beta-thalassemia patient treated 22 months ago today in another NEJM paper, and Frangoul will report on seven beta-thalassemia and three sickle cell patients tomorrow at the online ASH meeting. The CRISPR results are really very impressive, says Boston Children's stem cell biologist Stuart Orkin, whose lab discovered the BCL11A switch that led to both trials. (He is not directly involved with either.)

The results are comparable to the older strategy from Bluebird that relies on a different genetic alteration: adding a gene for an adult hemoglobin that has been tweaked so it reduces polymerization of the sickling form. At the ASH meeting, Thompson will give an update on about two dozen sickle cell disease patients who received the treatment within the past 3 years. As of March, the 14 with a follow-up of 6 months or more had experienced just a single mild pain crisis overall.

The Bluebird treatment was approved in Europe in 2019 for certain beta-thalassemia patients, and the company expects to seek Food and Drug Administration approval in the United States for its products for both diseases within the next few years. Bluebird chief scientific officer Philip Gregory says the long-term data for the firm's treatment give it an advantage over the newer approaches. Weve set a very high bar, he says.

Others who treat these diseases say its too early to crown a specific genetic treatment the winner. For example, reversing the fetal hemoglobin off switch, as the new CRISPR and RNA-based gene therapy strategies do, allows blood cells to make natural levels of the protein. But so far there are no signs that Bluebirds treatment results in excess adult hemoglobin that causes problems, Williams says. And although a virus-carrying gene can land in the wrong place and trigger cancer, CRISPR could similarly make harmful off-target edits. There has been no sign of that. Still, We need long-term follow-up for all the strategies, says the National Institutes of Healths (NIHs) John Tisdale, a coleader of the Bluebird study.

None of these genetic treatments seems likely to immediately help the many patients in places like Africa and India who dont have access to sophisticated health care. Itswonderful, but it wont solve the global health problem, Orkin says. Bluebird expects to charge $1.8 million for LentiGlobin in Europea sum it derived from looking at a patients gains in life span and quality of lifeand the other genetic treatments are likely to be similarly expensive. Costs will also include the chemotherapy needed to eliminate patients diseased blood stem cells, and the attendant hospital stay.

Bluebird and other groups are exploring whether antibodies, instead of harsh chemotherapy, can wipe out a patients diseased cells. In a bolder effort, NIH and the Bill & Melinda Gates Foundation last year announced a plan to put at least $100 million into developing technologies that would modify blood stem cells in a patients bone marrow by injecting the gene-editing tools themselves into the body. Its a big hairy goal, but its an engineering challenge, says gene therapy researcher Donald Kohn of the University of California, Los Angeles, who leads another sickle cell treatment trial. Well get there.

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CRISPR and another genetic strategy fix cell defects in two common blood disorders - Science Magazine