UCLA scientists advance stem cell gene therapy for deadly blood disorder alpha thalassemia major

Thanks to groundbreaking in-utero blood transfusion technology, what was once a fatal diagnosis in the womb can now result in live births. However, this medical advancement created a new challenge: a growing population of children born with that diagnosis - the severe, inherited blood disorder alpha thalassemia - which requires lifelong specialized care.

But a UCLA research team led by gene therapy pioneer Dr. Donald Kohn is developing a one-time stem cell gene therapy treatment for this condition that's potentially curative. The study findings are detailed in Cell Reports Medicine.

"This work really began when Dr. Tippi MacKenzie, a pediatric surgeon at UC San Francisco who was treating these cases, reached out to us," said senior author Kohn, a distinguished professor of microbiology, immunology and molecular genetics and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "She recognized that our gene therapy approach could be exactly what these children needed."

A proven, personalized medicine approach

Individuals born with alpha thalassemia major are missing all four copies of the genes required to produce hemoglobin. Without hemoglobin to carry oxygen in the blood, patients face serious health issues, including a lifelong dependence on blood transfusions, severe organ damage and early death due to iron overload.

While a bone marrow transplant from a matched donor could be curative, finding a compatible donor is often difficult, and the procedure carries the risk of graft versus host disease, a life-threatening condition in which transplanted cells attack the recipient's body.

The UCLA research team's gene therapy eliminates both challenges.

Instead of relying on donor cells, the therapy involves collecting a patient's own blood stem cells, adding the missing alpha-globin gene, and then returning the corrected cells back to the patient.

"The idea of a blood stem cell gene therapy is to fix the disease at the DNA level," said first author Eva Segura, a postdoctoral scholar and an alumna of the UCLA Broad Stem Cell Research Center Training Program.

To get the alpha-globin gene into the DNA of patient cells, the researchers use a viral vector - a modified virus that has the unique ability to deliver genetic information into a cell's nucleus without causing infection.

In alpha thalassemia major patient cells provided by MacKenzie, the gene therapy successfully restored normal alpha-globin protein production to healthy levels, enabling the modified cells to produce functional hemoglobin.

Kohn has successfully developed gene therapies for several hematologic diseases using a similar technique, including a cure for ADA-SCID, a type of severe combined immunodeficiency that leaves children without an immune system.

"Here, we're tackling a different disease but using a very similar approach," Kohn said. "If we can correct enough cells - as we've shown in this preclinical study - the results should be lifelong once we transplant them back into the patient."

Fulfilling a personal mission

For Segura, this work represents a full-circle moment.

As a UCLA undergraduate student, she learned about Kohn's gene therapy for ADA-SCID that successfully restored immune function in 48 of 50 children with the condition.

"Something just clicked, and the way I viewed research forever changed," she said.

The realization that life-changing medical breakthroughs were happening in the next building over galvanized her to go on to graduate school, where she joined Kohn's lab for her doctoral research and is now making her own contribution to a team known for turning cutting-edge research into life-saving therapies.

"I've always wanted to make a positive impact on people's lives, but I never wanted to be a physician," Segura said. "Working on gene therapy is the perfect fit - I get to stay in the lab doing research I'm good at, while still getting the opportunity to make a meaningful difference for patients."

Looking forward

The team has been awarded a grant from the California Institute for Regenerative Medicine to complete preclinical studies and prepare a pre-investigational new drug package submission to the U.S. Food and Drug Administration, the first step toward launching a clinical trial to evaluate the therapy in humans.

"More babies with alpha thalassemia major are surviving birth than ever before, thanks to in-utero blood transfusions," Kohn said. "Now we're working to give them the chance at a completely normal life, free from a lifetime of medical dependence."

Additional authors include Kevyn Hart, Beatriz Campo Fernandez, Devin Brown, Kevin Tam, Andrea Gutierrez Gracia, Eva Seigneurbieux, Karen Li, Carol Mulumba, Emma Blakely, Katelyn Masiuk, Roshani Sinha, Devesh Sharma, John Everett, Matthew Hogenauer, M. Kyle Cromer, Frederic Bushman and Tippi MacKenzie.

The research was supported by the National Institutes of Health, the California Institute for Regenerative Medicine, the Rose Hills Foundation and the UCSF Center for Maternal-Fetal Precision Medicine.