Brian Kaspar speaks with a soft but determined voice, choosing every word carefully.
The 45-year-old researcher, who serves as chief scientific officer of US-based gene therapy company AveXis, is extremely focused. This has helped him in his pursuit to develop gene therapy for patients suffering from deadly motor neuron diseases.
During his long career in the field, Kaspar often received feedback that his approach was too bold and was doomed to fail because gene therapy might not offer an efficient avenue to treat diseases affecting the brain and spinal cord.
Kaspar never took such criticism personally. He knew that the roller-coaster history of gene therapy had created a wall of skepticism in the scientific community. But he was also confident that meticulous, step-by-step research would break down this wall and convince skeptics that gene therapy could prove valuable to patients in need.
“[As scientists], we need to remind ourselves to be smart, to take bold action, to think big. But when you think big, be razor-focused on a singular problem. One baby step can be something bold that opens up a world of opportunity.”
The rise of gene therapy
The idea of manipulating a patient’s genes to treat and prevent diseases was initially proposed in 1967 by Nobel laureate Marshall Nirenberg. Twenty years after Nirenberg’s thesis, the first gene therapy trials were conducted. In 1989, at the National Institutes of Health, Steven Rosenberg and French Anderson performed the first gene transfer, using altered T-cells (a type of white blood cell) to treat patients with skin cancer. A year later, Anderson used a modified virus to transfer healthy genes to treat two children suffering from a hereditary immune disorder.
Despite these early breakthroughs, gene therapy received negative attention at the turn of the millennium when a young patient died during a trial. The tragic incident led to massive public criticism and harsher regulatory scrutiny.
Hunting for a virus
Trust in gene therapy was eventually restored as researchers gradually refined the strategies developed by pioneers such as Rosenberg and Anderson. Rather than taking big leaps, they worked to understand every single step involved in the genetic process.
One of these scientists was Kaspar, who for years worked at Nationwide Children’s Hospital in Columbus, Ohio, in the US. While there, he searched for new ways to develop a gene therapy to treat Lou Gehrig’s disease (also known as amyotrophic lateral sclerosis), a rare neurological disease that weakens patients’ muscles.
As part of their research, Kaspar and his team focused on viral gene therapies. With other technologies, such as chimeric antigen receptor T-cell (CAR-T) therapy, genes are modified outside a patient’s body. In viral gene therapy, however, researchers use specially designed viruses that are either stripped of their disease-causing properties or carry no human pathogens. The viruses retain their ability to reach inner organs and cells, where the healthy genes can be activated.
Finding the right virus is incredibly hard because there are so many of them. After years of research, Kaspar and his colleagues struggled to find a viral vector – a delivery tool to transport the healthy gene – that would reach nerve cells and cross the blood-brain barrier to transport genetic material to the right place. “We were close to ending our search, as nothing seemed to work properly,” Kaspar recalls.
A researcher works at an AveXis R&D facility in San Diego, California, in the US.
They did not give up. The team started to experiment with non-replicating adeno-associated viruses (AAVs). Although these naturally occurring viruses – which are not known to cause disease – are generally too big to cross the blood-brain barrier, the team hit upon a distinct virus with unusual properties.
“We took a very systematic approach to test some of the family-tree members of the AAV class,” Kaspar says. “And by 2008, we hit upon a virus that had this remarkable capacity to do something we had essentially never seen before.”
The virus crossed the blood-brain barrier at unprecedented levels and reached nerve cells in the spinal cord at efficiencies not previously seen. In the past, researchers considered it a success when a few brain cells were reached. The new virus, however, appeared to affect the entire brain. “This was really a eureka moment,” Kaspar says.
Given the virus’ unique ability to cross the blood-brain barrier, Kaspar and his team decided to focus on another rare motor neuron disease called spinal muscular atrophy (SMA). Patients with this condition are missing a functional gene that controls nerve cells in the spine. As a result, they are unable to send signals to their muscles, which progressively weaken and affect their ability to breathe. The disease can be so crippling that many children suffering from its most severe form often die or require permanent breathing support before reaching the age of 2.
In mouse models, Kaspar and his team were able to show the effectiveness of their gene therapy approach. “It was amazing,” Kaspar says. “In our tests, we not only showed that we could help prolong the lives of these mice almost tenfold. These animals were running around like normal, healthy mice.”
Keeping a razor-sharp focus
After extensive testing, Kaspar – who by 2013 had helped establish AveXis – was ready to start investigational human trials with children suffering from a severe form of SMA. But he and his team faced an uphill battle. “We were told many times how wrong we were, how we should not do this,” Kaspar says. “But we utilized science and we kept checking and rechecking our work to understand that we had control and that we had a safety profile in multiple species that gave us confidence.”
Kaspar’s razor-sharp focus on science paid off, however. The trial results were positive. AveXis received an FDA breakthrough designation in 2016, helping to expedite the development of its investigational gene therapy, which is currently being reviewed by health authorities.
Kaspar and his team are not stopping there. Kaspar leads research efforts at AveXis, which has grown into a company of more than 400 people and is now part of Novartis. He plans to further develop the technological platform to treat other neurological gene defects.
“I think the success that we had in spinal muscular atrophy has opened up the doors to other types of the disease and may pave the way for the treatment of other widespread monogenic disorders,” says Kaspar, noting that the journey will not be easy. “It’s a long way. But by keeping our focus, we hope to move the needle on these diseases.”