Can poliovirus fix spinal cord damage?

Motor-nerve cells in the spinal cord, which carry signals from the brain to muscles and glands, don't regenerate once injured--with long-term consequences for accident victims. If scientists could somehow infiltrate and reawaken these neurons, spine damage might be reversed.

Nature, as it turns out, may provide the perfect agent for such a mission--the poliovirus. The debilitating effects of poliomyelitis arise because the virus adroitly finds and invades motor neurons, which it then destroys.

Researchers have now devised a version of the virus that is harmless but still capable of locating and entering motor neurons. In tests on mice, the researchers show that this disabled poliovirus can deliver a batch of genes to neurons, a first step toward inducing wounded neurons to regenerate, says study coauthor Casey D. Morrow, a virologist at the University of Alabama in Birmingham.

Morrow and his colleagues used mice genetically engineered to produce the same poliovirus receptor molecule found in people. The protein appears in greatest abundance on the surface of motor neurons, which explains how the virus latches onto these cells.

The researchers disabled poliovirus by removing its capacity to make its shell. This stifles the virus' ability to spread from the invaded neuron to others and cause disease. Next, the team injected some mice with a version of the virus that included genes that encode a harmful protein; other mice received an innocuous version.

Mice given the benign treatment fared well, whereas mice receiving genes encoding the destructive protein had problems walking and suffered damage to neurons and cells that surround them. The test indicated that the modified virus, called a replicon, was delivering its genetic cargo to neurons and that these genes directed the cells to produce and release abundant amounts of the specified protein, the researchers report in the September NATURE BIOTECHNOLOGY.

In this study, the replicons' effect was short-lived. Mice that received the version that encoded the harmful protein largely recovered within a few weeks. This is exactly what the scientists had hoped, Morrow says.

In theory, a few days might suffice to manufacture some prized proteins in place of the experiment's destructive one. Morrow would like eventually to deliver replicons containing genes that encode proteins that shore up damaged neurons and rejuvenate nearby supporting cells. Reactivated neurons ideally would extend tendrils called axons to "rewire" broken or frayed nerve connections in the spinal cord, he says.

Because of the short-term effect of the genes in the replicon, therapy using the modified virus might require repeated doses. Morrow says mice in his laboratory have received up to six doses of the modified poliovirus without any harm.

The replicon's short shelf life might prove particularly useful in treating inflammation. Swelling exacerbates tissue injury in spinal cord trauma. A replicon encoding an anti-inflammatory protein, such as interleukin 10, might limit such damage, Morrow says. Scientists, however, wouldn't want to unleash a gene that indefinitely shuts off any immune reaction, even an inflammatory one, he says.

John R. Bethea, a neuroscientist at the University of Miami School of Medicine, says that the poliovirus-replicon work represents "a marvelous approach." Bethea envisions that if this therapy was to prove safe and effective in people, paramedics someday carrying syringes full of replicons that would enable accident victims to manufacture anti-inflammatory agents.