University of North Carolina at Chapel Hill
Asklepios BioPharmaceutical, Chapel Hill
Delivery of minidystrophin gene using modified AAV vector
Estimated start date for clinical trial
"Academic settings are fantastic for making discoveries, but not structured to do translational type research, such as developing a product,” says Jude Samulski, a virologist and professor in the Pharmacology Department at the University of North Carolina at Chapel Hill. “The academic setting was never meant to be a conduit for developing a concept into a product, and we knew that we had to step out in order to do that.”
Unlike most virology specialists, who have concentrated on infectious diseases, Samulski has always been interested in figuring out how to make viruses deliver genes. As a graduate student at the University of Florida in Gainesville in the early 1980s, his thesis project was developing AAV as a vector for therapeutic genes.
Working in the laboratory of Assistant Professor Nicholas Muzyczka (now a professor of molecular genetics and microbiology at the University of Florida), Samulski had started his career by studying another vector candidate, simian virus 40, or SV40. “Through those studies, we determined that that was not going to be an ideal vector, and we then shifted our interest to AAV, which was really very uncharacterized at that time. My job was take the virus apart and figure it out.”
Eventually, Samulski, with Muzyczka as mentor, isolated what’s now known as type 2 AAV and made it available to scientists. It’s been used for gene therapy trials in the lung disease cystic fibrosis and in several other settings, Samulski says. “It’s what we would call the parent virus that everybody started with.”
Samulski moved to the University of Pittsburgh in 1986, joining the Biology Department as an assistant professor with a laboratory to oversee. His first student was Xiao Xiao, a graduate student who had just come from China. Xiao proved an able and eager learner who focused on the lab’s AAV vector project.
In 1993, Samulski moved to the University of North Carolina and assumed directorship of its new Gene Therapy Center. Xiao moved first into industry, then to UNC and back to Pittsburgh in 1998.
“He continued to work on muscle biology,” Samulski says, “while we stayed focused on the vector aspects, the delivery system.”
A merger of ideas
At Pittsburgh, Xiao developed a miniaturized version of the gene for dystrophin, the muscle protein needed by people with DMD. Anxious to test it in a vector, he contacted his former mentor.
“He was looking for a way that he could take this into the clinic,” Samulski says. “We had just finished demonstrating that we could make clinical-grade virus for another genetic disorder called Canavan’s disease, an enzyme deficiency disorder. We were the first academic institution to ever make FDA-certified AAV vectors to go into the brains of children with Canavan’s disease. So we had cut our teeth and had a little bit of a track record by 2002, and that’s when Xiao approached me.” (Gene therapy trials in Canavan’s disease are under way.)
Xiao said he wanted to put his new minidystrophin gene into an AAV vector and test it. “He wanted to know if UNC could make the virus, and that’s when I told him that UNC had just spun out this company, Asklepios, and that we were using this virus for Canavan’s disease and for other efforts. We had started improving the vectors, and we came up with some new ones that we thought were better for muscle.”
Xiao and Samulski put their projects together, and Asklepios acquired the intellectual property rights to Xiao’s uniquely miniaturized dystrophin gene.
“Before that,” Samulski says, “it was a gene-delivery company, but we had no genes. Now, with the minidystrophin gene, we became a muscle-specific gene therapy company, working on muscle disorders.” (Asklepios has since trademarked its dystrophin gene-vector combination as Biostrophin.)
Samulski, Xiao and others put together a scientific and administrative team for Asklepios. Meanwhile, neurologist and clinical researcher Jerry Mendell at Ohio State University in Columbus had become convinced of the soundness of the plan and agreed to collaborate with the group and to direct the proposed clinical studies. (Mendell, a longtime MDA research grantee, co-directs the MDA clinic at OSU Hospital.)
In 2003, the group met with the Food and Drug Administration. “We proposed to them the new vector that we want to use and the minidystrophin gene, and they’ve helped us map out a study that they require in mice before we can move into patients,” Samulski says.
One such study is under way, he says, and the second will probably be completed by this spring. Then, there are other regulatory hurdles to jump, among them the approval of the Recombinant DNA Advisory Committee (RAC), a panel of experts under the umbrella of the National Institutes of Health that reviews clinical trials involving gene transfer, mainly from a safety perspective.
Samulski and the Asklepios team took their case before the RAC last month, and they’re now reviewing feedback on their proposal. “Since there have already been a number of AAV trials, we’re hoping that there won’t be a major impediment for us to go forward,” he says.
Samulski believes his group has the winning combination of minidystrophin gene and viral vector — now a slightly modified version of type 2 AAV. “We assume that we’ve engineered it to be a more efficient delivery system compared to its parent.”
Last year, MDA granted Asklepios $1.6 million for development of DMD gene therapy strategies.