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Alan Dove, PhD
Contributing Editor 

Though policymakers initially recruited big pharmaceutical companies to develop countermeasures against bioterrorism, most of the field’s players are actually small.

In October 2001, while the ruins of the World Trade Center were still smoldering at the southern tip of Manhattan, Americans suddenly received more bad news:
 
A hand-held injection/electroporation system for DNA vaccines, which can be used by non-physicians in field or clinical settings. (Source: Ichor Medical Systems) 
someone was sending weaponized Bacillus anthracis through the nation’s postal system. When the clouds of suspicious powder finally settled, five people were dead, 17 others had been hospitalized, and countless millions had begun hoarding antibiotics in their home medicine cabinets. The perpetrator remains at large.

The government’s initial response to the anthrax attacks included an innovative, multi-billion-dollar effort to jump-start a nascent biodefense industry. By offering large grants and a guaranteed market, officials hoped the program, called Bioshield, would entice leading pharmaceutical companies to develop new strategies against anthrax, smallpox, and other "select agents."

The result was somewhat different. "Bioshield was really intended to get big pharma to show up. Big pharma didn’t show up, and a lot of small microcap and nanocap companies like ours showed up [instead]," says James Joyce, CEO of Aethlon Medical, San Diego, Calif. While the press of small companies into a business designed for big ones has created some problems (see sidebar), it has nonetheless spurred some promising strategies.

A shot in the arm
Most biodefense drug development focuses on the six "Category A" diseases identified by the US Centers for Disease Control (CDC), Atlanta, Ga., as the biggest worries: anthrax, botulism, plague, smallpox, tularemia, and viral hemorrhagic fevers. Besides frightening pathology, the conditions all share a lack of acceptable vaccine and treatment options.

For several of the Category A diseases, researchers have the advantage of knowing that the problem is solvable. The smallpox vaccine, of course, predates modern medicine, and aggressive antibiotic treatment can cure plague. But side effects, suboptimal efficacy, and the potential for malevolent modification of pathogens with modern molecular techniques have left defense agencies scrambling for more flexible solutions.

Most of the biotechnology companies in the field are simply applying their core platform technology to multiple diseases, including some with bioterrorism potential. Alphavax Inc., Research Triangle Park, N.C., for example, is using its proprietary alphavirus-based vaccine system to target smallpox, Marburg virus, and other biodefense threats, as well as HIV, influenza, and cancer. The company can plug a variety of antigens into the alphavirus vector, which also makes the system more adaptable than traditional vaccines, if a new pathogen or bioterror agent emerges suddenly.

An even more flexible approach, which first excited vaccine developers more than a decade ago, is the DNA vaccine. When researchers first discovered that mouse muscle tissue will transcribe and translate naked DNA injected into it, the possibilities seemed limitless. Reducing those possibilities to practice, however, has been tricky.

"A lot of people have put an awful lot of effort into DNA vaccines hoping that the injection . . . into the mouse, which worked really well, could translate into the human," says Bob Bernard, president and CEO of Ichor Medical Systems, San Diego, Calif. Unfortunately, "as you scale-up from a mouse to a rat to a rabbit to a primate . . . the naked DNA expression level drops off exponentially," explains Bernard.

The main problem in scaling up DNA vaccines seems to lie in the equipment. Electroporation is the standard technique for delivering naked DNA to mouse muscle, but in animals with more muscle
 
A blood-filtration cartridge, packed with nanofibers that bind viruses while letting blood cells pass through. The cartridge can be inserted into the loop of a standard dialysis machine. (Source: Aethlon Medical) 
mass, it becomes harder to direct the DNA and the electric field to the same cells. Ichor is addressing the problem with a proprietary hand-held electroporation unit that simultaneously injects and electroporates at a single site.

"It’s an integrated device where the entire procedure is reduced to the simple push of a button," says Bernard. That simplicity is especially important in biodefense. Emergency planners expect that a major bioterror attack will overwhelm the normal healthcare infrastructure. Device manufacturers who can simplify vaccine delivery for non-physicians could enjoy a special edge in this market.

Ichor’s experience in the field also highlights the unusual way biodefense work has developed. Traditionally, defense contractors bid on specific jobs, then build their businesses around those contracts. With most of the biodefense work now driven by basic researchers and biotech startups, the field has more of an academic pace. Most companies in the field rely heavily on NIH grants for support, and relationships with defense agencies are developing through collaborative research rather than big supply contracts.

"Some of the impressive data that we’ve been able to generate with anthrax has provided the basis for some of these discussions within the Department of Defense to look at Ichor’s technology for some of their DNA vaccine leads," says Bernard. Army researchers, for example, are now collaborating with Ichor to test a DNA-based malaria vaccine with the company’s delivery technology.

Good for what ails you
Companies focusing on biodefense vaccines are aiming for an obvious customer: the CDC’s Strategic National Stockpile, a mountain of medical supplies that already includes millions of doses of vaccines and antibiotics. Current response plans call for sending
A corporate casualty in the war on bioterror
On Apri 5, VaxGen, Brisbane, Calif., held a conference call to give its investors the closest thing it could muster to good news. "Vaxgen and HHS have reached a settlement agreement that releases both parties from all liabilities associated with our anthrax vaccine contracts," said James Panek, the company’s CEO.

VaxGen’s $877.5 million contract with the US Department of Health and Human Services (HHS) had been canceled in December, after a series of high-profile revelations about missed milestones and irregular accounting at the company. Under the contract, HHS could also sue VaxGen for the snafu, but the settlement lets the company off the hook.

This Pyrrhic victory did little to dampen investors’ ire, and Lance Ignon, VaxGen’s vice president for corporate affairs, ended the 30-minute call as participants’ questions became progressively more pointed.

VaxGen’s problems have turned it into the poster child for what many see as the failure of Bioshield, the ambitious $5.6 billion effort to revamp the nation’s preparations for sudden disease outbreaks. The company’s spectacular flameout has also scared big and small drug developers, most of whom are now reluctant to stake their futures on biodefense.

"What probably concerns me about it the most is you’re developing a technology . . . for a business that you believe exists within the government, but you’re not really sure," says Bob Bernard, president and CEO of Ichor Medical Systems. Like most companies in the field, Ichor now focuses much of its effort on prevalent diseases like HIV and cancer, with side projects in biodefense.
 
portions of the stockpile out in "push packages," air freight-size containers that could reach any point in the country within 12 hours of an official request.

But no matter how fast the packages arrive or how much current technology they contain, most biodefense experts agree that they would be of little use against some agents. In an outbreak of viral hemorrhagic fever, or after a large release of a protein poison like ricin or botulinum toxin, the current standard of care is largely palliative. Worse, in a bioterrorist attack or sudden disease emergence, casualties will likely mount for days or weeks before public health officials can even identify the cause. How does one treat an unknown disease?

At least one company thinks it has an answer to that question. "[Our technology] has broad-spectrum capability to target the clearance of known pathogens, and in many cases perhaps genetically modified or emerging unknown pathogens," says Aethlon’s Joyce.

To accomplish that, Aethlon is taking a remarkably direct approach: physically removing viruses. The core of the company’s technology is a cartridge filled with hollow nanofibers, all coated with lectin proteins. The nanofiber pores are large enough to allow viruses and toxins through, but not whole blood cells. Because many animal viruses and toxins bind lectin proteins with high affinity, the system absorbs these nonspecifically.

The cartridge—a disposable, single-use unit—can be inserted into the loop of an ordinary dialysis machine, where it filters the blood passing through. Indeed, the company’s first clinical trial, which concluded recently in India, tested the system in 10 dialysis patients. A follow-up study is now underway in the US. Besides showing that the cartridges are safe, the initial study revealed that they can remove human viruses from circulation; a patient with hepatitis C saw a 52% decrease in viral load after a single treatment.

Joyce concedes that decreasing the circulating titer of a virus is not the same as curing it, but he argues that, in many cases, simply tipping the odds in the patient’s favor may be enough. "It’s known in many acute Category A pathogens that if you can reduce the titer of a pathogen in the blood to a certain extent, the immune system can be in a much better position to overcome the virus and clear the infection," says Joyce. The company also hopes the system will boost the effectiveness of antiviral chemotherapies against hepatitis C, HIV, and other chronic infections.

Meanwhile, other companies are hoping to reduce the need for broad-spectrum treatments by slashing the time required to diagnose an outbreak. In the second article in this series, scheduled for our September issue, we’ll explore the burgeoning field of rapid biodefense diagnostics.

About the Author
Dove is a freelance writer based in New Haven, Conn.

This article was published in Drug Discovery & Development magazine: Vol. 10, No. 5, May, 2007, pp. 26-28.

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