Dr. Katherine High is one of gene therapy’s pioneers, who has contributed to a long list of firsts in the field. As President of Spark Therapeutics, Dr. High led the team that developed Luxturna – the first FDA-approved gene therapy in the world and the first to be approved in both the US and Europe. Prior to that, her trailblazing clinical work with adeno-associated viral (AAV) vectors helped paved the way for many subsequent gene therapies. Today, Dr. High continues her cutting-edge work as President of Therapeutics at gene therapy company AskBio, a wholly owned subsidiary of Bayer AG. We spoke with Dr. High about the evolution of this fascinating field, which has the potential to provide transformational therapies for so many people with otherwise untreatable genetic diseases.
This article by Amy LeBlanc was part of a series on gene therapy in the lead up to Science for health 2022 where Dr. Katherine High opened the day with a keynote talk, giving an overview of gene therapy and how the field is evolving.
Q: Let’s start with the basics: What is gene therapy?
Katherine High: “Fundamentally, gene therapy treats or prevents genetic diseases by correcting problems in a person’s DNA. Often this is done by delivering a healthy version of a missing or defective gene into the cells in a specific type of tissue, such as the liver or the retina. One of the most common delivery methods is to use a viral vector to insert the healthy gene into the target cell.
“There are two main benefits to gene therapy: a single treatment can last a very long time, and the therapeutic effects can be truly transformational.” – Dr. Katherine High
“All that being said, gene therapy is in reality much broader than this classic definition, which doesn’t really encompass activities at the vanguard of the field. New delivery modalities are on the rise, and people are pushing the boundaries on what type of genetic edits are possible. There are also blurred lines between gene therapies and other related techniques like CAR-T or even mRNA vaccines. The field is very much still evolving.
“There are two main benefits to gene therapy: a single treatment can last a very long time, and the therapeutic effects can be truly transformational. If you’re missing a gene which results in a blinding disorder, for example, then inserting and stabilizing that gene in long-lived retinal cells can lead to a one-and-done type of therapy that remains effective for years or even potentially a lifetime, fixing the underlying cause of the disease altogether.”
Q: How has the field evolved?
Katherine High: “People started considering the potential of gene therapy in the 1960s, though the first clinical trials didn’t get underway until the 1990s. For most of that decade, the therapies were deemed safe, if ineffective. But then in the late 1990s and early 2000s there were some high-profile, serious adverse events that in some cases resulted in patient death. This led to a broad retrenchment in the field: early interest from pharmaceutical companies faded away, and even large biotechs specialized in rare diseases decided that gene therapy was too risky.
“So, in the early 2000s, gene therapy retreated back into the domain of the academic medical centers, where trials were smaller and more aimed at one-off treatments than commercial drug development. Slowly, in a few of these centers, positive results began to accumulate, and by the late 2000s we started seeing the first examples of real success. These positive clinical data kicked off a resurgence of interest in the field. One after another, new companies were created, like bluebird bio and Amsterdam Molecular Therapeutics (AMT).
“In 2017, the FDA approved its first gene therapy: Luxturna – developed by our team at Spark Therapeutics together with investigators from the University of Pennsylvania and the University of Iowa – for the treatment of a rare form of congenital blindness.” – Dr. Katherine High
“Finally, after decades of work, the EMA approved the first gene therapy in the world: uniQure’s Glybera, approved in 2012 for a rare disorder called lipoprotein lipase deficiency. Then, in 2017, the FDA approved its first gene therapy: Luxturna – developed by our team at Spark Therapeutics together with investigators from the University of Pennsylvania and the University of Iowa – for the treatment of a rare form of congenital blindness. Luxturna was later also approved by the EMA, making it the first gene therapy to be granted market authorization on both sides of the Atlantic. Since then, there have been about half a dozen gene therapies approved around the world, with many more clinical trials currently underway.”
Q: What progress can we hope for in the next few years?
Katherine High: “We’re anticipating several high-profile regulatory rulings this year and next, including for Zynteglo (bluebird bio’s lentiviral vector for beta-thalassemia), which has already been given conditional approval by the EMA and is expecting an FDA ruling soon. The first gene treatments for hemophilia A and B have also been filed: BioMarin’s therapy Roctavian for hemophilia A is likely to be given full approval by the EMA; and CSL Behring/uniQure has filed for approval with both the EMA and FDA for their therapy EtranaDez in hemophilia B.
“Another very exciting development is CRISPR Therapeutics and Vertex’ gene editing drug for beta-thalassemia and sickle cell disease. That is still in Phase III trials, but they have presented very impressive clinical data. An approval in sickle cell disease would be an extraordinary advance for patients, because it is a severe disease affecting a lot of people who currently have limited treatment options.”
“When gene therapy demonstrates its treatment potential in diseases like sickle cell disease, hemophilia, and Duchenne muscular dystrophy, it will be an absolute game changer for the field.” – Dr. Katherine High
Q: What will the impact be if these new gene therapies are approved?
Katherine High: “It would be a very big deal for the whole field if the hemophilia and sickle cell disease treatments are approved, as these are much larger indications than for any previous gene therapies. Of the indications currently approved, even a smart medical student would struggle to tell you much about them – they are all very rare. But we’re starting to see an increased number of clinical trials for more common diseases, like two Phase III trials ongoing for Duchenne muscular dystrophy (a fatal neuromuscular disease affecting young boys).
“I think that when gene therapy demonstrates its treatment potential in diseases like sickle cell disease, hemophilia, and Duchenne muscular dystrophy, it will be an absolute game changer for the field, because there is a lot of public awareness for these more common conditions.”
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Q: Why have most gene therapies approved so far been in rare diseases indications?
Katherine High: “One of the reasons so many gene therapy companies failed in the 1990s was that they were trying to do drug development at a point where we still had a lot of unsolved technical challenges. People in the medical centers – like our lab at the The Children’s Hospital of Philadelphia – started solving some of these critical problems in the 2000s, but this academic work mainly resulted in gene therapies that only worked for very specific indications. Because the technology was still at a place where you had to ask first ‘What can my vector do?’ and only then ‘What disease can I address?’. I think the difference between then and now is that many of these problems have progressively been solved, allowing for industry-driven drug development and expansion into a broader area of diseases.”
Q: What are the different modalities currently in use and under development?
Katherine High: “So far, all gene therapies approved have been for gene transfers – the addition of healthy genes when they are either missing or defective. People are also working on gene silencing (like gene knockdown using RNA interference in Huntington’s disease), but nothing has been approved yet. Most therapies developed to-date add healthy genes to target cells using viral vectors: either a retroviral vector (which is falling out of favor); a lentiviral vector (which seems safer); or an AAV vector (which is currently the most common).
“We’ve started seeing the rise of gene editing techniques like CRISPR being used… Although I think we will see the persistence of AAV for some time, gene editing will likely become an increasingly common modality in the future.” – Dr. Katherine High
“More recently though, we’ve started seeing the rise of gene editing techniques like CRISPR being used, for example in the CRISPR/Vertex gene therapy for sickle cell disease. Although I think we will see the persistence of AAV for some time, gene editing will likely become an increasingly common modality in the future. And there are other strategies in even earlier development, like base editing, which have yet to enter the clinic.”
Q: What are your hopes for the future of gene therapy?
Katherine High: “In the short term, I really hope to see gene therapies approved for single-gene disorders with large patient populations such as hemophilia and sickle cell disease, particularly for conditions which have never had a disease modifying treatment, like Duchenne muscular dystrophy.
“This field is still dawning – I am excited for all the future ‘firsts’ we’ve yet to see in gene therapy.” – Dr. Katherine High
“A longer-term goal for me would be the use of gene-based strategies to tackle complex acquired disorders, like heart failure or neurodegenerative diseases. I think gene therapy may have a big role to play not only in treating disease but also in preventing it. In age-related macular degeneration, for example, we already know that there are protective alleles and risk alleles, so gene therapy may be a way to ward off blindness. In diseases like Parkinson’s or Alzheimer’s, you may need to deliver multiple protective genes, but this is already something we are technologically capable of doing. This field is still dawning – I am excited for all the future ‘firsts’ we’ve yet to see in gene therapy.”
