Gene Therapy Pioneers Win 2026 Breakthrough Prize 

Genetic diseases impact almost 70-80 million people worldwide. Oftentimes, there are limited treatments that doctors can provide, leaving patients with few interventions to manage symptoms.

Recently, though, gene therapy has completely shifted the potential to care for many diseases. Advances in knowledge of responsible genes and nucleic acid technology have revolutionized the ability to specifically edit regions of the genome to correct mutations.

Today (April 18), the Breakthrough Prize Foundation awarded the Life Sciences prize to two teams of five researchers who pioneered gene therapies for two different types of genetic diseases. Physician scientist Jean Bennett, retinal surgeon Albert Maguire, and physician scientist Katherine High from the University of Pennsylvania developed a treatment to cure retinal blindness that is currently in use in the US, Canada, Australia, and Switzerland. Separately, clinical investigator Swee Lay Thein, now at the National Heart, Lung, and Blood Institute, tracked down the gene responsible for continued production of fetal hemoglobin in beta thalassemia and sickle cell disease and, with the help of physician scientist Stuart Orkin at Harvard University, brought this finding from the bench to the bedside.

An Eye for Gene Therapy

In the mid-1980s, Bennett became interested in gene therapy’s potential despite the technology only being in its infancy. “I realized, ‘Wow, this could be a great tool to treat a disease at its roots,’” she recalled.

Around the same time, Maguire learned that many disorders that led to retinal degeneration were caused by mutations in a single gene. Having met Bennett at Harvard Medical School for their medical training, he asked her about the potential to treat these diseases with gene therapy. She agreed that it would be easy to do this hypothetically but not so much in practice. “We didn't know any of the genes. We didn't have any animal models. We didn't have the tools. So, we had to develop all of that,” Bennet said.

Nonetheless, the two embarked on the project with the methods and knowledge that they had. In the early 1990s, a gene for one form of retinal degeneration was identified, steering their direction.¹ Bennet and Maguire used an adenovirus edited to prevent its replication to deliver the correct version of this gene to the mouse retina.^2-4 While initially successful, Maguire said, “It was very frustrating because while you could get transfer, the durability was not very good.”

To overcome this limitation, the duo switched to adeno-associated virus (AAV) that was also replication-deficient as a vector because AAVs lasted longer in retinal cells. Around the same time, the two explored using dogs as a model for retinal degeneration therapy. Unlike mice, the eyes of dogs are similar in size and anatomical structure to those of humans, and their response to vision impairment is more noticeable, making it easier to confirm when a therapy successfully restored their sight. In 1999, they successfully delivered green fluorescent protein to dogs’ retinas using AAV.⁵

Around the same time, researchers identified retinal pigment epithelium 65 (RPE65) as the gene responsible for a congenital form of eye degeneration.⁶ Although associated with childhood blindness in humans, it can occur in dogs too, and Bennett and Maguire were lucky that a trio of puppies were born with the exact mutation. “[The disease] was just strikingly similar in the way it manifested clinically [to humans],” Maguire said.

Using their recombinant AAV model, the two showed that they could successfully restore vision in dogs by reintroducing the correct version of RPE65.⁷ The dogs, now able to run around and play, captured Bennet and Maguire’s hearts with their friendliness, and the pair adopted two of them.

Over the next few years, they demonstrated that the gene therapy delivery technique, which Maguire developed specifically for this surgery, did not induce toxicity and led to a stable treatment in dogs.^8-10 Finally, the team was ready to bring their therapy to the clinic.

Maguire admitted that he was skeptical. Working in the clinic, he recalled how much false hope he saw patients put towards therapies that ultimately never worked. However, the first trials demonstrated safety and moderate improvements in humans, with more vision restored in children compared to adults.^11,12 Maguire recalled how he used an objective assessment to determine vision restoration by shining a light into the eye that received the therapy or not, and he watched only the treated pupil constrict. “At that point, I said, ‘This works. This is going somewhere.’”

Bennett and Maguire teamed up with High, who studied blood clotting factors and gene therapies and had experience with drug regulatory processes and manufacturing. Together, they developed Luxturna as a gene therapy for blindness due to an RPE65 mutation, and in 2017, the FDA approved it for patient use.

“The field of gene therapy continues to make extraordinary strides toward safer, easier, and more effective gene delivery, and more patients are benefiting from these extraordinary medicines every year. As one who has devoted much of my scientific career to the quest to turn genes into medicines I look forward to the day when genetic medicine can offer solutions for nearly all genetic diseases,” High said in an email.

Reflecting on the work, Bennet said, “There have been so many eureka moments, starting with seeing the puppies being able to see for the first time. That was just like outstanding to be able to see how their lives had transformed, and then seeing the same thing with humans.”

Indeed, Maguire, who performs the retinal surgery he developed, watches as timid children become curious and independent once their vision is corrected. “Seeing that transition, I mean, it’s amazing,” he said.

Upon learning about receiving the Breakthrough Prize, Bennett said, “I was shocked and thrilled and completely humbled and honored.” She added that she felt like they were accepting the award on behalf of their many colleagues who worked with them over the years. To this, Maguire compared it to a football coach accepting the Super Bowl trophy. “I am happy to accept this on behalf of the team,” he said.

Exploring Variability in Genetic Blood Diseases

Around the same time that Bennet and Maguire set out on their ambitious project, across the pond,, Thein joined hematologist David Weatherall’s lab at the Medical Research Council as a clinical fellow and began studying why people with beta-thalassemia had variability in their disease presentation. “I’ve always been interested in trying to predict severity because it will help us align the more risky treatments with the burden of the disease,” Thein said.

For her project, Thein recruited patients from the United Kingdom and their families to donate blood so that she could study differences that could explain the variable disease presentation. Other researchers in the field already knew that if a patient produced fetal hemoglobin, a blood protein normally only expressed during development, then that person was more likely to have a milder disease. Thein suspected that this was due to one or more genes.

One of the patients that she met with was from a large family that extended across Europe and Africa into Malawi. She traveled to the country to meet with these family members and collect their blood, eventually acquiring samples from 270 people. From this work, she identified a gene on chromosome 6q that had a variant in people in this family that contributed to fetal hemoglobin production.¹²

However, other people with high fetal hemoglobin production did not have this variant, leaving Thein with just as many questions as she had at the start of her project. She said, “I was kind of in the roadblock, if you like, and I had to first find out, is it worth chasing those genes?”

Around this time, Thein had a colleague who was recruiting twins for unrelated research. Thein thought that a similar approach could help determine whether genetics was a component in the variability of fetal hemoglobin production. Comparing identical and non-identical twins, Thein saw a clear genetic contribution to fetal hemoglobin expression, giving her the confidence to continue searching for the involved genes.¹⁴

In 2000, Thein moved to King’s College London, where she started caring for patients with sickle cell disease, another genetic disorder with similar outcomes as beta thalassemia, including the production of fetal hemoglobin. Thein decided to leverage the emerging genome-wide association studies to continue searching for genes that influenced variable production of fetal hemoglobin. Using these techniques, she identified B cell lymphoma/leukemia 11A (BCL11A) as a differentially expressed gene between individuals with high and low production of fetal hemoglobin.¹⁵

Prior to Thein’s study, BCL11A was known for its role as a transcriptional repressor in immune cell development and cancers related to these cells, making its appearance in regulating fetal hemoglobin surprising.^16,17 The following year, though, a different group also identified BCL11A in beta thalassemia. “It became clear that this was a gene that was involved in controlling fetal hemoglobin in adults,” Thein said. “This shows the power, also, of an agnostic approach, that you're not biased when you choose candidate genes.”

Thein’s group and others continued to study how BCL11A exerted its effect, eventually showing that it bound to regulatory regions in its target genes, including those for fetal hemoglobin.^18,19 “Stuart [Orkin]'s lab then whittled this down to a small area that now they've exploited for genome editing,” Thein said.

Orkin’s group studied BCL11A further, exploring how it worked as the “off switch” for fetal hemoglobin and how to safely manipulate its function in sickle cell disease.^20-24 Eventually, his team developed the approach that led to Casgevy, the FDA approved gene therapy for beta thalassemia and sickle cell disease.

Thinking about watching her work go from discovery to the clinic, Thein said. “I'm thrilled. I'm excited. I mean, I was first interested in trying to understand how to predict severity, so to build up a panel of genes and then to now see that being exploited therapeutically, it's just great.”

Despite this exciting success, Thein added that it’s sobering to realize that the gene therapy is still out of reach for many of the people who need it most. Because of this, Thein’s work today focuses on developing oral drugs for sickle cell disease as well as continuing to explore gene variations for this disease in different populations, since differences in fetal hemoglobin do not explain all of the variability.

Thein said that when she first received the phone call from the Breakthrough Prize committee, she ignored the call because she thought it was spam. After a member emailed her and asked her to take their call, she said “I was kind of stunned. I couldn’t believe it for a while.”

As the shock wore off, though, she said that she was grateful to be recognized for her work, and she was even more thankful for her colleagues, trainees, the families, and the volunteers that she worked with throughout the years who trusted her along the way.