It could be the first treatment for a terrifying problem faced by people with diabetes – the nerve damage that's a leading cause of amputations. A new drug being tested in people with diabetic nerve damage uses a patient's own genes to treat them.
Diabetic neuropathy nerve damage, which causes a loss of sensation in the hands and feet, can allow small injuries to go unnoticed and become severely infected, to the point where amputation is the only option. Tight control of blood sugar can keep neuropathy at bay, but there is no cure.
"There are a variety of medications that are available now that can help with the pain but unfortunately, there's nothing available to help with numbness or prevention of nerve damage," says diabetes specialist Mark Kipnes, MD, director of the Diabetes and Glandular Disease Research Clinic in San Antonio, Texas.
But now Kipnes is leading the first human testing of a new drug that might prevent or even reverse such damage. Designed by researchers at Sangamo Biosciences, the drug uses a natural protein that turns on the patient's own gene for helping nerve growth. As the researchers wrote in the journal, "Diabetes," tests on diabetic rats showed that repeated treatments with the drug led to increasingly improved nerve function.
Sangamo biochemist Philip Gregory notes that this Phase 1 clinical trial is the first human test of an entirely new class of drug that could turn any gene on or off, depending on the disease. "These proteins are natural proteins that exist in essentially every human cell, there are thousands of them, they naturally regulate genes in cells," Gregory explains.
These gene-regulating proteins have an important feature called a zinc finger domain. The zinc finger region, whose structure was discovered by Nobel laureate Aaron Klug, is a finger-shaped structure containing a zinc atom. Unlike most proteins, those with these special domains can actually bind to DNA and act as transcription factors – telling specific genes to turn on or off.
"So what we're able to do is to engineer these proteins so that they can bind to different genes of our choice," says Gregory. In this case, the gene targeted by the Sangamo team was one encoding a protein called VEGF-A, a natural growth factor.
"In diabetes, patients have significant blood sugar changes that give rise to the production of toxic byproducts in tissues that drive, essentially, a poisoning of the nerves," says Gregory. He explains that because VEGF-A naturally stimulates regeneration of nerves and the blood vessels that nourish them, it can reverse the damage caused by the glucose-driven degeneration.
"It's not that diabetic patients lack the gene for VEGF-A," explains Gregory. "They continue to have the gene and they produce VEGF-A, but it's like the patient's cells don't realize they could be more protected or suffer from the disease much less if the cells produce more of this particular protective factor."
While patients in the Phase 1 trial tolerated the drug well it needs to be tested for longer time periods to prove its safety – particularly since this treatment would need repeated administration. As Gregory explains, "Obviously this is a chronic disease and we need to have a chronic treatment, if you like, for such a disease." More than half of the 185,000 amputations in the U.S. each year are a result of diabetes, a disease that plagues an estimated 20.8 million Americans -- seven percent of the population -- and is on the rise.
Kipnes is excited about the prospect of having a treatment to offer people with diabetic neuropathy, but he points out that there may be some risks. As he points out, injecting a growth factor into the body could theoretically encourage other, unwanted things to grow. "So these patients are very carefully screened for any kinds of cancers and tumors," he says.
The researchers report there's been no evidence of carcinogenesis in their extensive animal studies. They also say that some patients in the safety trial showed some anecdotal improvement in their nerve function.
Kipnes is currently recruiting patients for a second safety trial as well as a larger Phase 2 trial of the drug's effectiveness. Both are scheduled to begin later this year.