Cancer, says Dan Rodgers, is a hellish parade of horribleness.
Cancerous cells multiply aggressively, interfering with the normal function of healthy organs. Tumors secrete hormones and other chemicals that exploit the body’s own defenses to the cancer’s advantage. Your body knows something is wrong, so stress hormones are released in an effort to inhibit growth processes and channel nutrients to the brain.
Deprived of resources, muscles begin to atrophy. Washington State University muscle biologist Rodgers, together with colleagues at the Baker Heart and Diabetes Institute in Australia, investigated treatments for tumor-induced muscle wasting called cancer cachexia. The research was so promising that Rodgers founded AAVogen, a company dedicated to bringing the therapy to market.
For Rodgers, it’s personal. “My dad died of pancreatic cancer. He didn’t die from the tumor metastasizing. He died because of extreme muscle loss.”
Cachexia can be fatal but, more often, it reduces a patient’s mobility and quality of life—as does muscle wasting in muscular dystrophy. That’s the condition for which Rodgers and his team think they may have found a treatment.
Myostatin, a protein that blocks the growth of muscle and helps optimize muscle mass, normally limits muscle growth, which is metabolically expensive to produce. Their treatment blocks the action of myostatin with a gene called SMAD7. Blocking myostatin in animals can result in double-muscled cattle, like the Belgian Blue.
Myostatin inhibitors have been tested in clinical trials to treat muscular dystrophy and cachexia but they worked outside the cell. “So if you injected one of these inhibitors in the circulation, they’d block myostatin from working on every tissue, not just muscles. They’d also block other hormones that are structurally very similar to myostatin,” Rodgers says. Administering a myostatin inhibitor outside the cell can result in nasty side effects that weaken blood vessels and cause internal bleeding throughout the respiratory system.
AAVogen’s solution is to deliver the inhibitory gene directly to muscle cells using an attenuated virus that co-evolved with humans and does not cause disease. “This works via injection but the virus only sticks to cardiac and skeletal muscles,” Rodgers says. “The virus is recognized by a receptor, and the virus—and its therapeutic package of DNA—are engulfed by the cell. Once in the cell, the therapeutic package goes into bioreactor mode.”
In other words, it starts reproducing and doing its therapeutic work.
Rodgers says, “You don’t need to infect 100 percent of the cells in a muscle. If a few cells recover, the whole muscle is going to be better.”
The first goal is to get FDA approval for the targeted gene therapy to treat muscular dystrophy. To that end, late in 2017 AAVogen received a $2 million infusion to run FDA Phase II toxicology and safety studies that are the prerequisite to human clinical trials.
“Our therapy increases the efficiency of the heart, so we could potentially treat heart failure, as well,” Rodgers says. Which means, he points out, that athletes will want it to build up heart muscle. “Gene therapy is on the anti-doping radar.” AAVogen is also developing an assay to determine if a person has been exposed to the delivery virus or has SMAD7 in muscle cells.
Rodgers says he gets dozens of emails a week from people whose family members have muscular dystrophy and who have seen his papers in scientific journals. “I spend several hours a week trying to answer questions,” he says.
His urgency is palpable, not only because he lost his father to a potentially reversible condition but also because of another family member with muscular dystrophy. Flicking a tear from the corner of his eye, he straightens up in his chair, determined, relentless, back to work.