New drugs, fresh from the barnyard

They have four legs, fuzzy faces and udders full of milk.

To the uninitiated, they look like dairy goats. To GTC Biotherapeutics Inc., they’re cutting-edge drug-making machines.

The goats being raised on a farm in central Massachusetts are genetically engineered to make a human protein in their milk that prevents dangerous blood clots from forming. The company extracts the protein and turns it into a medicine that fights strokes, pulmonary embolisms and other life-threatening conditions.

GTC has asked the Food and Drug Administration to OK the drug, called ATryn. An expert panel voted overwhelmingly Friday that it is safe and effective, putting it on the verge of becoming the first drug from a genetically engineered animal to be approved in the U.S. The agency is expected to make a final decision in early February.

If approved, the drug would be followed by perhaps hundreds of others made from milk produced by genetically engineered goats, cows, rabbits and other animals. Other products in the pipeline are designed to treat people with hemophilia, severe respiratory disease and debilitating swollen tissues.

“As soon as we were able to make genetically engineered animals, this was an obvious thing to do,” said James Murray, a geneticist and professor of animal science at UC Davis. “It’s totally cut-and-paste. This is kindergarten stuff with molecular scissors.”

The biotechnology industry is rooting for ATryn. The FDA’s endorsement would signal to Americans that they have nothing to fear from the futuristic technology -- and suggest that the millions of dollars they’ve invested in the technology could soon begin to pay off.

If the drug is approved, “it takes a big question mark off the table in terms of products that are developed from this technology,” said Samir Singh, president of U.S. operations for Pharming Group, which is developing medicines using milk from genetically engineered cows and rabbits.

The public has had misgivings about eating food from genetically modified animals, and some vocal critics of such technology say the wariness could extend to medicines.

“I think many people are going to have the same revulsion,” said Jaydee Hanson, a policy analyst at the Center for Food Safety, a Washington advocacy group that opposes genetic manipulation of food and animals.

For scientists, the appeal is obvious. Many drugs are now synthesized in bioreactors by bacteria or Chinese hamster ovary cells, and they require extensive processing to be suitable for human use. Genetically engineering animals is a more straightforward alternative for producing proteins, which form the basis of all biological drugs.

“We’re taking advantage of the fact that the mammary gland was designed by nature to make proteins,” said Tom Newberry, GTC’s vice president for government relations.

The process of designing animal milk with human proteins starts by identifying the human gene containing instructions for making a medically useful protein. That human DNA sequence is combined with pieces of animal DNA that regulate when and where the protein is produced. Those regulatory controls ensure that the human gene is only switched on in the mammary gland during lactation and doesn’t interfere with any other part of the animal’s body.

The DNA package can be injected into a single-cell animal embryo with a microscopic needle, though it’s a hit-or-miss proposition. When the embryo divides, it may or may not incorporate the foreign DNA into its own genome. The embryo is then transferred to the uterus of a surrogate mother, with a 1% to 3% chance that it will result in a healthy animal containing the human gene.

A more advanced alternative is to start with a normal animal cell and splice the DNA package directly into the cell nucleus. The modified cell can be cloned to create a new animal that expresses a human gene. With three to five founder animals, a company could use traditional breeding methods to create an entire herd of genetically engineered cows, sheep or goats.

“Something like five or six cows can produce the world’s requirement for some drugs,” said Murray of UC Davis. Demand for most drugs could be met with herds no bigger than 50 cows or 100 goats, he said.

Companies separate the components of engineered animals’ milk based on their size, shape, electrical charge and other chemical characteristics. The process ultimately leads to vials of pure protein that carry out specific functions in the human body.

The species of animal depends in part on the volume of protein needed or how quickly it needs to be produced.

The companies say it’s cheaper to create the animals than to build and maintain expensive bioreactors. The technique could make it cost-effective for companies to develop drugs to treat diseases that affect relatively few patients.

To make ATryn, GTC used the microinjection technique to insert the human gene for antithrombin alfa into goat embryos. The protein is essential for preventing blood clots, but about 1 in 3,000 to 5,000 people are born with a genetic defect that prevents them from making enough of it.

Most patients are treated with standard blood thinners like warfarin, which can be dangerous for those undergoing surgery or childbirth. In those situations, patients are treated with antithrombin protein extracted from human plasma.

But the supply is limited. If all the plasma donated in the U.S. each year were used to make antithrombin, the most that could be produced would be about 100 kilograms. “We can match that with 150 goats,” Newberry said.

GTC plans to expand the use of the protein beyond patients with the genetic defect to include people who have a short-term deficiency due to burns or other traumatic injuries, he said. The European Commission approved ATryn in 2006.

The company’s scientists have made more than 100 proteins in the milk of genetically engineered animals, Newberry said.

The company is considering clinical trials for factor VIIa and factor IX proteins to treat hemophilia, along with alpha-1 antitrypsin to treat severe respiratory problems, he said.

Pharming, based in the Netherlands, plans to seek U.S. and European approval this year for Rhucin, made from a human protein purified from the milk of genetically engineered rabbits. The protein, C1 esterase inhibitor, helps control inflammation. Patients with hereditary angioedema have a genetic mutation that prevents their bodies from making enough of the protein, and the result can be severe swelling, abdominal pain and airway obstruction.

Pharming is focusing on cows to make other proteins in larger quantities. The company is working with the U.S. Army on cow milk containing human fibrinogen, a protein that helps blood to clot, Singh said.

Other companies are using genetic engineering to make milk with proteins for vaccines, a class of cancer drugs called monoclonal antibodies, and nutritional supplements.

Regulators will have their work cut out for them as they try to anticipate all the potential risks posed by genetically engineered animals and the medicines they produce, said Greg Jaffe, biotechnology director at the Center for Science in the Public Interest, a consumer advocacy group in Washington. Hanson, of the Center for Food Safety, said he fears animals created through genetic engineering and cloning are inherently unhealthy due to the unnatural circumstances of their birth, despite FDA assessments that the animals are fine.

“We don’t want a herd of sick animals being our source of a new biological drug,” he said.

At the meeting Friday, FDA biotechnology advisor Larisa Rudenko said the agency’s Center for Veterinary Medicine found that GTC’s goats were treated very well and posed no environmental risks.

Those assurances won’t satisfy everyone, said Todd A. Winters, professor of animal physiology and biotechnology at Southern Illinois University in Carbondale.

But he said people should not let fear stand in the way of potential cures.

“You’ve got to weigh whether you’re going to save a life or not,” he said.

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karen.kaplan@latimes.com