'Biopharming' Offers A Powerful New Approach To Ebola And Other Diseases

Due to the largest-ever Ebola virus outbreak in Africa and the treatment of a handful of patients with an experimental drug, there has been a resurgence of interest in therapeutics to treat the disease. One aspect that has been largely ignored is that the drug, called ZMapp, a mixture of three varieties of humanized monoclonal antibodieswhich bind, in vivo, to proteins on the surface of the Ebola virusrepresents an exquisite tour de force of genetic engineering.

The drug is obtained from genetically engineered tobacco plants that have been infected with genetically engineered plant viruses. During infection of the tobacco plants over the course of a week, the viruses, which are completely harmless to animals and humans, produce huge amounts of the antibodies. The plants are then harvested and homogenized and the antibodies are purified and formulated for administration. They bind to proteins of the Ebola virus in patients and elicit a humoral (antibody) and cellular (lymphocyte) response to the virus.

A seminal study of ZMapp in monkeys experimentally infected with Ebola virus was reported last week in the journal Nature. All 18 rhesus macaques treated with the drug recovered, even when it was administered beginning up to five days after infection. According to the journals press release, Three doses of ZMapp, administered at three-day intervals starting on day three, four or five after rhesus macaques were infected with Ebola virus, resulted in the survival of all 18 animals, while the three rhesus macaques that did not receive ZMapp all succumbed to Ebola virus infection by day eight. The drug reversed severe Ebola virus disease symptoms such as excessive bleeding, rashes and elevated liver enzymes. These findings are particularly encouraging because they provide precisely the kind of evidence of efficacy needed for regulatory approval of ZMapp, which will be evaluated by FDA under the animal rule. This applies to the development of drugs when human efficacy studies are not ethical or feasible.

Obtaining medicines from plants is not new. Many common medicines, such as morphine, codeine, cocaine and the laxative Metamucil are all purified from plants. But the promise of a relatively new approach called biopharming lies in using genetic engineering techniques to induce crops such as corn, tomatoes and tobacco to produce high concentrations of high-value pharmaceuticals.

Biopharming emerged with great promise about 15 years ago, with clinical trials of vaccines and drugs made in bananas, tomatoes and tobacco. Unfortunately, the field confronted the zeal and risk-aversion of regulators. In 2002, a company called Ventria purified two human proteins from genetically engineered rice and found that when added to oral rehydration solution given to children with diarrhea, they markedly shortened the duration of symptoms and reduced the incidence of recurrence. This potential public health breakthrough has been effectively blocked by the FDA: In 2010 the company approached the Food and Drug Administration for recognition that these proteins, which are found in human tears and breast milk, are generally recognized as safe (a regulatory term of art), but received no response. Ventria was unwilling to market the product without the FDAs endorsement, so it isnt available, depriving children in developing countries of a life-saving therapy.

More than a decade ago, scientists at Arizona State University created a biopharmed vaccine against Norwalk virus, the bug that annually causes millions of cases of diarrhea on cruise ships and in nursing homes. This vaccine, initially produced in tomato fruit and more recently in tobacco leaves, is still being studied to find an optimal formulation for administration.

The field testing of biopharmed plants has proved particularly problematic. In 2003 the U.S. Department of Agricultures Animal and Plant Health Inspection Service announced onerous new rules for the field testing of biopharmed crops. That ended most entrepreneurial interest in biopharming. Mapp Biopharmaceutical, the privately-owned company that makes the experimental Ebola drug ZMapp, boasts a workforce of nine people and has been completely financed by government grants and contracts.

USDAs rules on the cultivation of the biopharmed plants in the field impose highly prescriptive, one-size-fits-all design standards, as contrasted with performance standards, which would specify an end-pointsuch as gene-transfer below a certain levelthat must be achieved by whatever means. USDAs regulation fails to take into account the actual risks of a given situation.

The ostensible objective of the regulation is to avoid biopharmed drugs contaminating food, if crop plants are used in the drug production. The food industry, including groups such as the Grocery Manufacturers of America and the U.S. Rice Producers Association, has raised NIMBYnot in my backyardobjections. They claimed that biopharmed plants could contaminate their food-grade crops, but that fear is overblown and can be avoided in several ways. Production in a non-food crop is an obvious one, and that has affected manufacturing decisions for many new biopharmed vaccines and drugs. For example, the developers of the Norwalk virus vaccine switched from tomato to tobacco both to improve drug yields and to avoid becoming embroiled in disputes with NGOs and regulators about the supposed risks of genetic engineering and possible contamination of food.

The risk of plant-made drugs getting into food products is now virtually nonexistent because the companies involved have switched to production in facilities with rigidly controlled environments, mainly using tobacco. This approach was greatly advanced by the investment in 2010 of more than $80 million in facilities by the federal Defense Advanced Research Projects Agency (DARPA) to expand the tobacco-growing capacity at several companies. The investment was driven by DODs desire to expand the nations ability to respond with new drugs and vaccines to emerging diseases or attacks with biological agents. These sorts of facilities, which have a high degree of control over growth conditions, are essential for the reproducible production of high-quality drugs. This constructive public-private collaboration set the stage for ZMapp, the Ebola drug, to be produced by one of the companies Kentucky Bioprocessing.

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'Biopharming' Offers A Powerful New Approach To Ebola And Other Diseases