by Cheryl Soohoo
Gene therapy delivers novel solution for treating serious blood disease.
They happened to be in the same room discussing the same thing: investigating curative therapies for beta thalassemia, an inherited blood disorder that causes severe anemia and requires lifelong blood transfusions for survival. That’s how Alexis A. Thompson, MD, MPH, professor of Pediatrics in the Division of Hematology, Oncology and Stem Cell Transplantation, recalls first meeting scientists from a small biotechnology startup called Bluebird Bio at a thalassemia conference six years ago. More than an exchange of business cards, though, this chance encounter evolved into an international multicenter trial testing a promising gene therapy approach that may revolutionize the treatment of beta thalassemia and related blood diseases.
The results of the collaboration were published earlier this year in a headline-making paper in The New England Journal of Medicine. The paper reported findings from an international gene therapy trial known as Northstar headed by Thompson, plus a separate, smaller study led by investigators in France. The two clinical studies evaluated a novel treatment strategy to replace the disease-causing gene — beta globin — responsible for beta thalassemia. When mutated, this gene impairs the ability of red blood cells to make normal amounts of hemoglobin. The phase I trials used a lentiviral vector manufactured by Bluebird Bio to deliver healthy copies of the beta globin gene into a patient’s harvested stem cells. Following transplantation of their genetically modified stem cells, the majority of the studies’ 22 participants no longer needed blood transfusions or required far fewer moving forward — a major breakthrough.
Scientists have been working for decades to develop genetic modifications to effectively treat inherited human diseases. Hemoglobin disorders such as beta thalassemia and sickle cell disease have long been a focus of this gene therapy research. “From the beginning, we recognized that if patients could produce enough normal hemoglobin, this approach could be transformative,” says Thompson.
Thompson is director of the Comprehensive Thalassemia Program at Ann & Robert H. Lurie Children’s Hospital of Chicago, a member of the Stanley Manne Children’s Research Institute and president of the American Society of Hematology, the largest hematology organization in the world.
“As soon as it was feasible to initiate a phase I clinical trial, we seized the opportunity to take all of this wonderful basic science work and apply it to two conditions for which it was clearly ideal: thalassemia and sickle cell disease,” she says.
Alexis A. Thompson, MD, MPH, professor of Pediatrics in the Division of Hematology, Oncology and Stem Cell Transplantation. Top image by Living Art Enterprises/Science Source. Above photo by Ann & Robert H. Lurie Children’s Hospital of Chicago
Seeking new options
An iron-binding protein in red blood cells (RBCs) called hemoglobin makes it possible for RBCs to transport oxygen and fuel cells throughout the body. Mutations in the gene for beta globin, an essential component of hemoglobin, adversely impact hemoglobin production: too little or none at all can deprive cells of oxygen and lead to fewer RBCs in general, usually causing anemia. The lives of individuals with the most severe form of thalassemia depend on blood transfusions every three to four weeks, usually starting before a patient is even one year old. With an estimated global prevalence of nearly 300,000, thalassemia is among the most common blood disorders in the world, affecting an estimated 60,000 infants each year.
While life-sustaining, frequent transfusions can cause a buildup of excess iron. Patients then require iron chelation therapy to remove the iron and prevent damage to organs such as the heart and liver, as well as to lessen side effects like joint pain and fatigue.
The only potentially curative therapy available to patients with transfusion-dependent thalassemia has been allogeneic hematopoietic stem cell transplantation (HSCT) — receiving normal blood-forming stem cells from a genetically similar donor. But not every eligible patient has an appropriate donor, and even under ideal circumstances, problems can arise from these stem cell transplants, such as rejection of the donor cells. In one serious complication, graft versus host disease, donor cells attack healthy tissues and organs in the transplant recipient. Late effects including infertility, growth retardation and poor bone health must also be considered prior to proceeding with HSCT. In general, young recipients with a well-matched donor and minimal iron buildup achieve the best outcomes.
Wanda Sihanath , 22, first patient to receive therapy in 2014
“There has been a real need to develop other definitive therapies for people who don’t have sibling donors or who are older,” says Thompson. “The use of gene therapy represents decades of research to attempt to actually restore or replace a defective protein such as beta globin with a new source of that protein.”
Collect, Modify, Return
Thompson and her colleagues at Lurie Children’s and Feinberg sprang into action once animal studies successfully demonstrated gene therapy could correct beta thalassemia as well as sickle cell disease in mice. The investigators participated in the early development of the clinical protocol that would be used for the Northstar study at sites in the United States, Australia and Thailand.
The experimental gene therapy starts with a thorough evaluation of potential recipients to ensure adequate organ function and their understanding of the potential risks and benefits of the protocol. Then, study sites collect stem cells from patients’ peripheral blood or blood stream via apheresis technology, which is less invasive than bone marrow harvest performed under general anesthesia. The cells are sent to a centralized U.S. manufacturing laboratory for insertion of the new “healthy” beta globin gene into the abnormal stem cells.
Zinnia Jones, 13, received therapy in 2018
With the largest pediatric stem cell transplant and pediatric apheresis programs in Illinois, Lurie Children’s is well suited to conduct this type of cutting-edge gene therapy research. The hospital’s stem cell transplant team oversaw the management and care of close to half of the global study’s participants.
“We have a highly experienced group of transplant physicians and nurses, adept at collecting stem cells from patients with complex conditions,” says Jennifer Schneiderman, MD, MS, ’06, ’07 GME, associate professor of Pediatrics and medical director of Lurie Children’s Therapeutic Apheresis Program. “Harvesting stem cells from thalassemia and sickle cell patients is not straightforward. Their red cells are not normally shaped, and the apheresis machine spins and separates them in a different fashion than what we typically see. Our expertise allows us to modify the equipment to obtain what we need.”
After six to eight weeks at the central processing laboratory, the reprogrammed stem cells are returned to the transplant centers. Patients return to the hospital where they first undergo a rigorous chemotherapy regimen before being reinfused with their gene-modified stem cells. They remain in the hospital for four to six weeks for the management of side effects.
“This therapy carries significant risks,” says Schneiderman, a hematologist who specializes in stem cell transplant. “These patients were very brave to take this leap of faith and try this treatment.”
How does the new therapy work?
The clinical trial included 22 patients with beta thalassemia from two studies. After undergoing the therapy, 15 patients no longer require regular blood transfusions to survive and seven patients reduced their need for future tranfusions by 70%. Illustration by MCKIBILLO.
At a median follow-up period of 26 months, the investigators found that 15 of the 22 patients, who were once transfusion-dependent, no longer required regular blood transfusions to survive. They also suffered no ill effects from the novel gene therapy. The remaining study participants who didn’t become transfusion-independent were able to reduce their need for transfusion by an average of 70 percent.
Building on the findings from the initial Northstar study, Thompson’s team has been working on phase II/III gene therapy studies. Expanded to include sites in the United Kingdom, Germany, Italy and Greece, these studies are focused on refining the gene therapy — better addressing the specific genetic subtypes of beta thalassemia and boosting the quantity of RBCs genetically modified by the lentiviral vector. For example, more participants with a genotype called non-beta-zero thalassemia who received gene therapy became transfusion independent than those with genotype beta-zero thalassemia. Additionally, increasing the amount of “healthy” genes taken up by cells appears to enhance the body’s ability to make adequate levels of normal hemoglobin. The results of these studies have prompted Lurie Children’s investigators and others to begin evaluating the use of gene therapy to treat sickle cell disease, another inherited blood disorder.
Some have already begun calling gene therapy the definitive “cure” for thalassemia. While not ready to use that four-letter word, Thompson is no doubt thrilled by the early success of this innovative treatment for blood disorders.
“We are incredibly gratified that everyone who participated has had clinical benefit, either the reduction or elimination of regular blood transfusions,” she says. “While we plan to follow these patients for a long time, I am very excited about the early stability of this treatment without serious side effects. We are absolutely headed in the right direction.”
source: Northwestern University