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Virus Particles Rebuilt to Boost Immunotherapies

Cut-away image of virus

Portion of virus’s outer protein coat cut away to reveal virus contents (Public Domain Images)

22 September 2015. Engineers at Stanford University redesigned a hepatitis virus from the inside out to make it a better vehicle to stimulate the immune system for treating disease. The team led by chemical and bioengineering professor James Swartz published its results yesterday in Proceedings of the National Academy of Sciences (paid subscription required).

Swartz is also a serial entrepreneur and founder of three research-based enterprises. Stanford University says it has a patent on the technology, which it licensed to a company founded by Swartz. One of those companies is Bullet Biotechnology in Menlo Park, California developing virus look-alikes to deliver immunotherapies for cancer and autoimmune diseases.

These virus look-alikes, called virus-like particles, are promising techniques for delivering treatments designed to stimulate the immune system. Viruses in nature are often quite effective in delivering infections, but these engineered virus-like particles are shown so far to be too unstable and do not combine well with therapeutic payloads. In addition, the particles by themselves can often generate an unwanted immune reaction, not the desired reaction to fight off a disease.

Swartz and colleagues decided to almost start from scratch in designing a virus-like delivery mechanism for immunotherapies. The team began with a hepatitis B virus, because of its larger size and structure that in principle should support delivering a biologic treatment. As with viruses in general, hepatitis B viruses contain a core of genetic material carrying the instructions that cause the infection and resulting disease.

The researchers focused on one of the outer layers of the virus called the capsid, made of proteins but providing only a framework to support the virus and not the cause of infections. Another key part of the engineered virus is the set of protein spikes protruding from the outer layer used to invade host cells. But they discovered modifying these outer surfaces of the virus would not by itself provide a vehicle that could reliably deliver therapies.

Instead, the team found it had to rewrite the DNA in the genetic material carried in the core of the virus to produce the desired solution. By editing the genetic code sequence in the virus’s core, they were able to assemble a virus particle that would be invisible to the immune system, yet stronger, and still behave like a virus.

The new genetic code produces particles without the tell-tale negative chemical charge on the capsid, by transplanting a small charge-free region of the outer spikes over the entire surface. Tests in the lab show the engineered particle does not produce an immune response in mice.

The researchers also strengthened the stability of the particle by introducing an artificial network of sulfur atoms that bond naturally with amino acids in proteins. But the edited genetic code can still make 240 copies of that code in the core’s material, under the capsid layer and outer spikes.

“We call this a smart particle,” says Swartz in a university statement. “We make it smart by adding molecular tags that act like addresses to send the therapeutic payload where we want it to go.” The virus-like particles still need to be further designed to carry those molecules on the outer spikes that identify targets, such as cancer cells, or addresses for specific cells or tissue in the body.

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