spent the bulk of his career trying to slip medicines through what’s known as the “blood-brain barrier,” a semipermeable lining of the blood vessels in the brain that is hard for drugs to penetrate. That night, it finally became possible.
Foust showed Kaspar microscope slides from mouse tissue indicating that a type of AAV virus, AAV9, could cross the barrier. They found it throughout the central nervous system, including the motor neurons in the spinal cord that control muscle function. They studied the slides for hours, in awe. The idea of using AAV9 to send a gene therapy into the brain and spinal cord became real. “What’s the first disease we target?” they asked one another, and they both came up with the same answer: SMA.
In SMA, a genetic mutation causes the lack of a key protein, SMN, which in turn leads to the death of motor neurons. The prognosis for Type 1 SMA, diagnosed in infants, is particularly grim. “Love them and prepare to say goodbye” is what clinicians would say to parents, Kaspar says.
Before the 2016 approval of the Biogen (NASDAQ: [[ticker:BIIB]]) drug nusinersen (Spinraza)—a chronic treatment that could change the trajectory of the disease—there wasn’t much clinicians could offer except palliative care. Could a gene therapy, with one dose, offer a long-lasting solution—or potentially a cure?
Their work on AAV9 crossing the blood-brain barrier was published in Nature Biotechnology in 2009. Kaspar went to work to find out if it could lead to a gene therapy. He used AAV9 to deliver SMN protein into mice engineered with an approximation, or “model,” of SMA. After one shot the mice started to survive for days, then weeks, months, and more than a year—much longer than they should have. He saw the same in monkeys. “That’s when we knew we’ve got to get this to patients,” Kaspar says.
But drug companies weren’t interested. There was “tremendous reluctance that this was real,” Kaspar says. So Kaspar teamed with biotech entrepreneur John Carbona in 2013 to form a company called AveXis, which licensed the therapy from Nationwide and raised at least $75 million in private capital to move it forward.
A major concern lay ahead, however. To succeed, AveXis had to inject infants with very high doses of AAV9 for the treatment to make a difference. Nationwide scientists had learned this through failure. Gene therapies delivered to isolated limbs or muscles weren’t going to “treat the core problem” of a neuromuscular disease, Rodino-Klapac says. To get enough of the medicine to all the key muscles affected—the heart, the diaphragm, and more—the gene therapy had to be given systemically at a high dose.
Mendell and Kaspar got calls from leaders in the field pleading with them to stop. “You’re going to kill someone,” Kaspar recalls being told. “This is going to be Jesse Gelsinger all over again.”
Mendell had to make the final call. It was he, after all, who had to do the procedure, who had to have the “iron clad stomach,” Kaspar says.
Many years later, Sarepta CEO Ingram asked Mendell why he picked such a high dose. “I’m sick of watching kids die, that’s why,” Mendell shot back, according to Ingram.
“Without that, we wouldn’t have saved lives and wouldn’t have had patients walking,” Mendell told Xconomy when asked about the risk.
The day of the first high-dose infusion came in 2014. Kaspar says that he made sure Mendell had a cup of coffee and a meal, patted him on the back, and watched him disappear into the hospital clinic. Kaspar and Carbona paced the rest of the day, waiting for updates. Finally, a call from Mendell: “Come meet the brave family and the real pioneer.”
Kaspar walked into the patient’s room. He saw
