Pig research gives hope for diabetes cure

By Jeff Sturgeon

BLACKSBURG

A Blacksburg medical company says it is a step closer to finding a potential cure for one form of diabetes, tapping pigs as a source of healthy, insulin-oozing cells that might someday be transplanted into ailing humans.

Revivicor Inc. and researchers at the University of Pittsburgh recently reported that by injecting sickened laboratory monkeys with live, pig pancreatic cells, they reversed the monkeys' Type I diabetes.

Tests on diabetic people could begin in two years and, if they are successful, it could usher in one of the first approved human medical treatments derived from living animal cells.

With a global epidemic of diabetes taking shape, medical researchers are looking for answers for people who can't make or effectively use insulin to convert food to energy.

The disease, which millions of Americans try to manage with medication, is considered incurable.

But Revivicor sees a day when regenerative medicine specialists will replace failing human body parts with healthy animal versions grown in virtually unlimited supplies and genetically altered for compatibility.

The monkey tests showed it can work in a laboratory, officials said.

"We now have survival and a complete cure of diabetes for one year in a monkey," said David Ayares, Revivicor's CEO.

Revivicor, a 21-employee, private company in the Virginia Tech Corporate Research Center, allowed University of Pittsburgh officials to announce the monkey results because the transplantations occurred there.

But the company's role is key and its contribution illustrates the sort of medical innovation coming out of the high-tech business community rooted in Southwest Virginia.

Ayares said the results achieved by the Revivicor-UPMC team are the best in the world in that one experimental monkey maintained a normal blood glucose level without injected insulin or special diet for slightly more than one year - versus six months in another company's experiment.

The results are reported in the December issue of the American Journal of Transplantation.

Diabetes cases expected to double by 2030. More work lies ahead.

Just to reach the start of human trials will cost at least $10 million and require two years of preparation. Human tests will run for three to five years after that, Ayares predicted.

Dr. R. Paul Robertson, one of two presidents of the American Diabetes Association, called the work important.

"Like most science, it's a step forward. They've done better using pig islets (pancreatic endocrine cells that produce insulin) than other people using pig islets before," Robertson said.

He called diabetes a "huge" threat, given a potential doubling of caseloads by 2030. Currently, 3 million people in the United States have Type I diabetes and 19 million have Type II, according to estimates.

The special technique is "not a complete home run," Robertson said, because the monkeys had to be given drugs to suppress their immune systems from attacking the transplanted cells.

A cure would work with few or no immunosuppressant drugs, which can debilitate the patient, he said.

Although immunosuppressive drugs were used, the monkeys remained healthy, researchers said.

According to Ayares, the team's goal is to use limited immune-blocking drugs - no more, say, than do patients who receive a transplant of human islet cells.

He said the advantage of the Revivicor method would be a virtually unlimited supply of transplant material (because pigs can be bred in virtually unlimited numbers).

Advocates of human islet cell transplant grapple with a severe shortage of donor islets that limits the number of transplants in North America, said Julia Greenstein, research program director at the Juvenile Diabetes Research Foundation.

For that reason, researchers are interested in the suitability of pig islets for transplant, she said, calling the Revivicor-UPMC work a step.

"There's a lot more that needs to be done before this gets into clinical testing under an FDA protocol," Greenstein said.

To be sure, moving insulin-producing islet cells from healthy pigs into lab monkeys with induced diabetes has been done before, but the beneficial cells did not survive long.

In this case, Revivicor brought to the table a batch of pigs that had been genetically modified to calm the rejection response.

Company has ties to Dolly the sheep

Revivicor, which employs recombinant DNA technology (altering an animal) and cloning (copying an animal), knew how to do that because it is a spinoff of the famous Scottish firm that first cloned a mammal from an adult cell - Dolly the sheep.

Back in the early 1990s, PPL Therapeutics Plc had become interested in a project in Blacksburg to produce human therapeutic proteins in livestock. PPL bought TransPharm, a company behind the project, from then-Virginia Tech faculty member Tracy Wilkins, because it wanted assets including microinjection facilities and a farm, Ayares said.

After Dolly was born in 1996 in Scotland, some cloning work got under way in Blacksburg at the old TransPharm, which was then known as PPL Inc.

It cloned a cow with a strategy to advance protein production in 1998 and cloned pigs with a goal to advance regenerative medicine in 2000. A group of Pittsburgh-based investors bought the pig side of PPL Inc. from the parent company in Scotland in 2003 to focus on regenerative medicine.

This spinoff became Revivicor. The investors were the University of Pittsburgh Medical Center, a 20-hospital, nonprofit health system based in Pittsburgh, whose International and Commercial Services Division holds a minority stake in Revivicor; Highmark Health Ventures Investment Fund LP, an investment vehicle of a Pittsburgh health insurance company that holds a small stake; and Fujisawa Investments for Entrepreneurship LP.

Since its inception, the company has also won grants worth $14 million, both from federal organizations such as the National Institutes of Health and Department of Defense and private sources such as JDRF, Ayares said.

The company has also benefited from valuable ties to the Virginia Bioinformatics Institute at Virginia Tech, which has provided DNA-related analysis, and the Virginia-Maryland Regional College of Veterinary Medicine, which has provided veterinary services, according to Ayares, who said Blacksburg will remain the company research and development headquarters long-term.

Now 7 years old, Revivicor operates on several fronts related to the prospect of transplant ing pig parts into people.

Two others are medical implants and whole organs for transplant. No recent news has been announced on those fronts, but the impression is that much is happening that goes unannounced for strategic reasons. Ayares said primates have lived up to six months on transplanted hearts and kidneys from Revivicor pigs.

Best results came from pig given a gene

In the latest flourish of activity that has been made public, researchers set out to cause and then cure diabetes in a monkey. It's all laid out in the American Journal of Transplantation article, which narrates events as the UPMC-Revivicor team worked.

They began by chemically inducing Type I diabetes in a group of nine macaque monkeys - destroying their insulin-making ability.

The doctors harvested insulin-producing cells from genetically modified pigs. The swine of the "large white" breed lost their lives as a result of the procedure.

Then, the sedated monkeys received one of several batches of pig cells via infusion through the portal vein, which leads to the liver. Within one or two days, the cells began producing insulin in ways that showed up on the monkeys' charts.

The monkeys survived the longest on islet cells from a certain, special pig. Revivicor had given the pig a gene that produces the human version of a cell surface protein involved in regulating how strongly the immune system attacks foreign bodies.

The monkeys' longevity told the researchers that the modification had, as desired, curbed the rejection response.

While several went three months, one monkey, identified as M7273, lived in a nondiabetic state for 13 months before researchers elected to end the experiment and he was sacrificed for examination.

"It probably would have gone longer," Ayares said.

Human testing will come after FDA approval.

What's next

Ayares said he expects the project team to submit an application to the Food and Drug Administration seeking clearance for human tests.

Ayares also said the company is designing what he called a clean, pathogen-free animal production facility to produce pigs for human studies. Where it will be built has not been decided, Ayares said.

Revivicor grew all of the pigs used so far at a facility in rural Montgomery County. About 150 animals live in temperature-controlled rooms on vegetarian chow.

Suyapa Ball, head of porcine technology at the facility, summed up the excitement of the small staff of animal technicians who work there.

"We are actually going to do something incredible if this works," she said.