It had been two years of not knowing what was wrong with their daughter, who since birth had spells of eye flickering, muscle contractions, pain and temporary paralysis.
Simon and Nina Frost took Annabel to the best neurologists until a diagnosis emerged: alternating hemiplegia of childhood (AHC).
For many of the 900 or so children affected by the ultrarare genetic disorder, mutations impair the body’s sodium potassium pump, which interferes with the firing of nerve cells. There is no treatment or cure, and any one of Annabel’s episodes has the potential to lead to brain damage or death.
AHC foundations informally recommend only four U.S. physicians. One was too busy to see new patients. Another had a two-month wait. And the few scientists who study the disease focus on research and not treatment.
So for the next two years, Simon Frost — a real estate investor with no background in science — pursued the science of AHC. He now leads an effort to develop a gene therapy that could one day lead to a treatment.
He said he felt the only way toward a treatment was to do it himself. When it comes to funding and research, “it’s not who needs it most, it’s who agitates and presents a compelling enough argument,” he said. “And to get to that compelling argument, you need money and sophisticated scientists.”
He is not the only parent who has come to this conclusion. There has been an explosion in the number of parents and foundations seeking gene therapies in the past five years, said Steve Gray, a molecular biologist and associate professor of pediatrics at UT Southwestern Medical Center. There are more than 7,000 rare genetic diseases like AHC, most without treatments.
Gray was hired by Frost and his partners last November to build and produce a “second generation” AAV vector. In this type of gene therapy, the adeno-associated virus is engineered as a vector to carry DNA that encodes a functioning gene into target cells.
Every few weeks, he receives an inquiry from a parent of a child with a rare disease looking to explore developing a gene therapy. “As a parent, you know that you would do anything — and everybody will say that they’ll do anything,” Gray said. “But it really is kind of a special breed of person that can actually do this.”
Frost approached his daughter’s illness the way he approached his businesses. While working with a Chinese company, he learned basic Chinese so he could understand his colleagues better. After Annabel’s diagnosis, he had to learn a new language.
He kept a glossary of unfamiliar terms as he pored over the medical literature. For a year, he would wake up at 3 a.m. to read before work, and then again at night and all weekend.
“I just wanted to understand what this disease was like at a molecular, cellular level,” he says. “And figure out what drugs and therapies there were available immediately because my doctors didn’t know.”
Frost placed an ad for a scientist who could work as a consultant and found Natalia Morsci, a cell and molecular biologist who has worked at National Institutes of Health.
After six months of studying the scientific literature with her, Frost began to formulate his concept for a gene therapy in which the adeno-associated virus delivers functioning genes to cells to compensate for dysfunctional ones.
Through the help of a member of Congress, Frost landed a meeting with NIH scientists.
Chris Boshoff, of the National Institute of Neurological Disorders and Stroke at NIH, was among those who met with Frost. Only later did he realize that “this guy’s actually studying this,” Boshoff said. “Like any other scientist.”
Frost later met with Gray at a gene therapy meeting in Chicago. At first, Gray was skeptical about whether AHC was a good candidate for AAV gene therapy. But after talking with Frost, Gray was impressed. He has seen other parents try to project manage to varying degrees, but he said Frost’s work was not typical.
Annabel, almost 4, is an inquisitive child. She can walk, though she’s a bit hunched. She enjoys interacting with people, although her motor loop difficulties limit her to speaking in one- or two-word phrases.
One afternoon at the Frost home, Simon Frost looked at a study on how efficiently the AAV vectors carry the gene into the mice brains. Annabel peers over, and he moves the computer so she can see, too.
When Frost talks about the project, he sounds like a scientist. When he talks about Annabel, he’s an adoring father.
When a university that had grown an AHC mouse line declined to share it, the setback was personal and painful. There was much more at stake than science. At stake were the things that Frost wants most for Annabel: to walk and talk normally, to be able to hold a job, to maybe have a family.
But it’s not just Annabel; there is a whole community of families with an AHC child relying on him to succeed.
A little bit of sperm from a male mouse would have saved a year for their project, Frost said.
“And when you’re sitting with a child, that’s a quarter of their life.”