When Katherine A. High entered the world of gene therapy, the concept was more theoretical than practical. She recalls the earliest attempts – and the earliest failures. But also the first real breakthroughs, and the patients whose lives were transformed forever.
Turning Genes Into Medicine
In her keynote as the recipient of the Bengt Samuelsson Award, Katherine High shared three decades of experience – a story of perseverance, innovation, and breakthroughs that have changed human lives.
She outlined three foundational breakthroughs in genetics: the discovery of DNA’s structure, the invention of PCR technology, and the sequencing of the human genome. But something else was just as crucial.
"Progress in virology, especially since the 1930s, was key," High said. "Thanks to the electron microscope, researchers could finally see virus particles – nucleic acids wrapped in a protein coat."
In the 1970s, the idea emerged to use modified viruses as delivery vehicles – vectors – to insert healthy genes into diseased cells. The viruses were stripped of their ability to replicate but retained their capacity to deliver genetic cargo into human cells.
The first clinical trials began in the early 1990s at the NIH in Bethesda, Maryland, targeting patients with severe inherited immune deficiency. But the early results were underwhelming.
Setbacks That Stalled the Field
In the early 2000s, the field suffered serious blows. A teenager in one clinical trial died from a toxic response to an adenoviral vector. In another, participants developed leukemia. Investors pulled out. Several virus vectors – like adenoviruses – were abandoned for the setting of genetic disease.
Momentum returned when adeno-associated viruses (AAVs) became the vector of choice. AAVs do not integrate into the host genome, making them safer, yet they enable long-term gene expression – especially useful for lifelong diseases.
High explained that gene therapy resembles surgery more than traditional drug therapy, often requiring only a single dose. Another difference: many gene therapies have been approved based on smaller clinical trials than standard pharmaceuticals.
“That tells you something about how powerful it is to reintroduce a missing gene in a disease that exists precisely because that gene is missing,” said High.
The Search for a Working Treatment
High shared her work on hemophilia B, an inherited X-linked disorder that causes lifelong deficiency in clotting factor IX, primarily affecting boys. Early results in animal models were promising, but trials in humans brought new complications.
In one patient, clotting factor levels improved dramatically – only to plummet weeks later. Researchers suspected an immune reaction. Was the body recognizing the modified virus as a threat? Understanding the immune system turned out to be crucial.
By mapping the immune response and tailoring the gene construct, High’s team achieved long-lasting effects in patients – at lower doses and with fewer side effects. The therapy was approved in Europe and Canada in 2024 after Phase 3 trials led by Pfizer.
A Fork in the Road – and a New Beginning
When external funding ran dry in 2004, High received support from her hospital to continue her studies – on one condition: that she also pursue therapies for other devastating childhood diseases. That led to a fruitful collaboration with Jean Bennett, a specialist in eye disorders.
Together, they developed a gene therapy for LCA2 – a rare inherited retinal disease caused by mutations in the RPE65 gene. Children with LCA2 are born with severely impaired vision and often go completely blind during their teens.
“Vision loss begins early,” High explained, “but the eye remains structurally intact for a while. That gave us a therapeutic window where gene therapy could work.”
The therapy used AAVs to deliver a functional copy of the RPE65 gene. The viral shell dissolves after infusion, leaving only the healthy gene. Researchers also added a short course of steroids to counteract inflammation. Then came the Phase 1 trial.
“Even at low doses, the improvements were dramatic,” High recalled. “One young woman called her doctor three weeks after treatment: ‘I opened my eyes and could see the furniture in my apartment.’ Others could finally see their phones.”
A video showed trial participants navigating an obstacle course – a sort of maze – before and a year after treatment. Initially, one participant couldn’t complete it. A year later, they walked through it with ease.
“Every therapy has its own challenge,” High said. “With hemophilia, it was the immune response and vector design. With the eye disease, it was about finding the right endpoints and navigating regulatory hurdles.”
High was deeply involved in the development of Luxturna – the first FDA-approved gene therapy for an inherited eye disease – through Spark Therapeutics, a company she co-founded.
Now, she looks ahead to the next generation of synthetic AAVs.
“These new capsids are more tissue-specific,” she said. “But the key is always to match the clinical need with what the vector system can actually deliver.”
Lessons From a Pioneering Career
According to High, most failures in gene therapy come down to two things: underestimating what it takes to achieve a therapeutic effect, or overestimating what the technology can deliver.
“The art of gene therapy lies in choosing the right disease targets,” she concluded. “And the golden rule is to use the lowest effective dose. Every bottleneck in development must be solved – even if it never earns you a Nature paper.”
Katherine High’s talk was a powerful reminder that genetics is not just about life’s code – but about courage, persistence, and the will to change lives.
