Altered Viruses Offer Hope in Treating Brain Maladies

Researchers are subverting some of nature’s most potent viruses--the infectious agents responsible for HIV, the common cold and herpes--to enlist them in defense of the ailing human brain.

In research presented Tuesday at a national meeting of the Society for Neuroscience, scientists outlined new experiments using genetically engineered viruses to penetrate the brain’s protective barriers and infuse its unique nerve cells with new genes to restore their health.

The altered viruses could be used to combat an array of neurological disorders, including brain tumors, Alzheimer’s disease, Parkinson’s disease and a variety of inherited maladies. They one day may even help alleviate the effects of brain damage caused by strokes.

Despite formidable technical hurdles, the new techniques already are showing preliminary success in laboratory experiments, they said. Federal health officials said the improved genetically engineered viruses may be ready to test on human beings within five years.

“There is a lot of excitement about the ability to introduce new genetic information . . . and the implications it has for diseases that affect the nervous system,” said Dr. Howard Federoff, a neurologist at the University of Rochester School of Medicine.

Domesticating a disease and then using it to rearrange the genetics of the brain is one of the most promising--and riskiest--enterprises in modern neuroscience, researchers said.

Until this fall, researchers had not attempted to alter the genetics of human brain cells, even though more than 100 different clinical trials of experimental gene therapy, aimed at correcting other medical conditions, are underway.

Many scientists believe that viruses are the ideal way to transport genes because they naturally infect cells to deposit genetic material. When it comes to treatments designed to alter the brain, however, researchers are worried that they could easily cause as much damage as the conditions they seek to cure.

Because the brain is so delicate and in such a confined space, researchers can introduce only small amounts of altered virus into the cranium, said Xandra Breakefield, who is experimenting with viral gene therapies at Massachusetts General Hospital. The “high infectivity” of a virus is especially important to deliver enough therapeutic material to brain cells, Breakefield said.

The challenge is to neutralize different viruses by removing their disease-causing genes and then tailor each of them to target different neural disorders. Toward that goal, the animal experiments reported Tuesday involved a range of altered viruses:

* In a preliminary experiment designed to disarm HIV, neuroscientist Fred Gage and his colleagues at the Salk Institute for Biological Studies in La Jolla were able to retain the virus’ ability to insert itself into brain cells to create a nontoxic virus. At the same time, Gage said Tuesday, his team successfully used the new virus, called a lentiviral vector, to deposit new genes into brain neurons. The new genes are active for at least six months, animal experiments show, meaning that they have had time to integrate into the life of the cell. “Whether these are adequate concentrations to have a biological effect, we don’t know,” he said.

* Turning the cold virus into a potential treatment for Parkinson’s and Alzheimer’s, researchers at New York Hospital-Cornell Medical Center and Rockefeller University have successfully used a modified version of the virus, called an adeno-associated vector, to inject genes into an animal brain, producing evidence that the new genes are activated inside nerve cells. The researchers eliminated most of the common toxic and inflammatory side effects of the virus. However, they acknowledged, the virus still provokes a response from the immune system, as if it were an infectious disease.

* Using the cold virus to treat a hereditary disease, researchers at the Iowa School of Medicine used a modified adeno-virus to successfully transfer the genes to treat Lesch-Nyhan syndrome, which affects the central nervous system. Working with laboratory animals, Beverly Davidson and her colleagues corrected the inherited disease. She is now testing the virus system against other metabolic disorders.

* Creating a treatment for brain cancer, researchers at Massachusetts General Hospital reported that they have used genetically engineered herpes virus to selectively destroy brain tumors in mice. Breakefield and her colleagues created a herpes virus that can multiply safely inside tumor cells. They used an enzyme produced by that virus as a catalyst to convert a nontoxic drug into a powerful destroyer of tumor cells. Healthy brain cells are unaffected.

Now her team is combining parts of the herpes virus and the cold virus to create an even more potent infectious anti-cancer vaccine.

At least one company has started clinical tests of an altered virus meant to treat brain tumors.

In September, Sandoz Pharmaceuticals Corp. began a worldwide trial using a genetically engineered herpes virus to treat patients with glioblastoma brain tumors, the most common and deadly type of primary brain tumor. They are using their altered virus to destroy tumor cells left in the brain after neurosurgery.

At the neuroscience conference, however, some researchers said not enough is known yet about the behavior of the modified viruses for them to be safely tested on human beings.

“People have gone to human trials too soon,” Gage said. “We don’t know enough about the long-term effects.”

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Making Viruses Beneficial

Researchers are turning infectious viruses into living remedies for brain diseases.

* The Procedure: Scientists strip a virus of its harmful toxic elements and insert into it new genes designed to treat a neural disorder.

* Why It Might Work: Viruses can put new genes into neural cells which, unlike other human body cells, do not reproduce.

* Who Could Benefit: Altered viruses one day could be effective against brain tumors, Alzheimer’s disease, Parkinson’s disease, stroke damage and some hereditary disorders.

* The Risks: Viral gene therapies could transmit a viral disease or disrupt normal brain functions.

* The Next Step: Lab experiments to ensure that the new viruses are safe.

* Quote: “There is significant progress being made.”

--Fred Gage at the Salk Institute for Biological Studies in La Jolla.