There has been an explosion in the number of parents and foundations seeking out gene therapies in the past five years, says 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, Gray says, most without treatment options


Finally a potential diagnosis emerged: alternating hemiplegia of childhood, an ultrarare genetic disorder. The Frosts' initial excitement at having answers quickly waned, however.

They learned that, for many of the 900 or so children in the world affected by AHC, mutations in one of the genes that code for a subunit of the body's critical sodium potassium pump interferes with the body's ability to repeatedly fire nerve cells. In addition to Annabel's other symptoms, difficulty breathing, choking and falling are common.

They also learned that there is no effective treatment or cure, that any one of Annabel's episodes has the potential to lead to permanent brain damage or death, and that it is hard to get information about the disease.

Foundations dedicated to AHC informally recommend only four physicians in the United States as knowledgeable enough about the disorder to see patients. Of those who are closest to the Frosts, who live in Washington, D.C., one was too busy to see Annabel.

There was a two-month wait to see the other one. The foundations themselves didn't have many answers to the Frosts' initial questions about life expectancy or what course Annabel's disease might take. The Frosts discovered that relatively few scientists and clinicians study AHC, and their focus seemed to be basic research and not developing a therapy.



The real estate investor and developer and former rugby player had no background in science, "but honestly," he says, "I felt like the only way to get towards any type of therapy for Annabel and AHC kids was to do it myself."




When it comes to funding and research for diseases, "it's not who needs it most, it's who agitates and presents a compelling enough argument," Frost says. "And to get to that compelling argument, you need money and sophisticated scientists."




There are more than 7,000 rare genetic diseases like AHC, Gray says, most without treatment options. He specializes in developing gene therapies for rare diseases for families and foundations and helps move them from pre-clinical testing into clinical trials.

Gray, who also serves as director of the UTSW viral vector facility, was hired by Frost and his partners last November to build and produce a "second generation" AAV vector. AAV stands for adeno-associated virus. In this type of gene therapy, the virus is engineered as a vector to carry DNA that encodes a functioning gene into target cells.


"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."



"I just wanted to understand what this disease was like at a molecular, cellular level," he says. "What was it doing to my child? And figure out what drugs and therapies there were available immediately because my doctors didn't know."




Chris Boshoff, a program officer at the National Institute of Neurological Disorders and Stroke at NIH, was among those who met with Frost to discuss his ideas for a gene therapy and how it might be funded. The two men stayed in touch. Only later did he realize that "this guy's actually studying this," Boshoff says. "Like any other scientist would do. So that is quite extraordinary."


Gray has seen other parents try to project-manage to varying degrees and says the level of Frost's work is not typical.

Frost decided early on against hiring one academic group to do all the pre-clinical work needed to develop a potential gene therapy, which many parents of children with rare diseases do, because of the associated high costs and long timelines. Instead, he contracts with a variety of research organizations in conjunction with Gray's lab. Frost recruited and collaborates with 20-plus doctors and scientists who are part of the broader project team.

"It's still very early stage, but they've done incredibly good work over the last couple of months to push this forward," Boshoff says.






Annabel, now almost 4, is an inquisitive and friendly child. She can walk, though she's a bit hunched over. It's clear from her frequent chiming in that she enjoys interacting with people, although her motor loop difficulties limit her to speaking in one- or two-word phrases. She's on a strict nap schedule — lack of sleep is a trigger for episodes.


When Frost talks about the project, he sounds like a scientist. When he talks about Annabel, he's an adoring father.

She's incredibly loving and caring, he says, and "spends her whole life wanting to make friends and learn things."

She loves choosing clothing for other people.



"It weighs on you," Frost said.

When a university that had already grown an AHC mouse line declined to share it because researchers thought Frost's project was duplicative, the setback was personal and painful. There was much more at stake than science. At stake were the things that Simon Frost wants most for Annabel: to walk and talk normally, to be able to hold a job, have a boyfriend and maybe a family.



"And when you're sitting with a child, that's a quarter of their life."