A valuable lesson in gene therapy

January 16, 2001

A YEAR after 18-year-old Jesse Gelsinger died following experimental gene therapy, researchers are beginning to understand what went wrong. Their work may help to prevent similar tragedies in the future.

Savio Woo of the Mount Sinai School of Medicine in New York opened the conference by recounting how Gelsinger died after he was injected with an adenovirus carrying a gene to treat his liver disorder. The incident sent shock waves through the field, and similar trials were quickly halted.

Federal agencies criticised the leader of the trial, James Wilson of the University of Pennsylvania, for not reporting adverse reactions in other patients, for example (New Scientist, 18 December 1999, p 9). But during the investigation, the National Institutes of Health's Recombinant DNA Advisory Committee learned that many other researchers had also failed to notify them of complications in gene therapy trials.

The manner of Gelsinger's death took scientists by surprise in a number of ways. Although the virus was injected directly into his liver, it infiltrated several other organs as well. And while liver inflammation was considered the most likely side effect, Gelsinger died from a widespread inflammatory reaction. Closer examination showed his blood had high levels of IL-6, a protein that promotes inflammation.

Now Wilson and his colleagues have done experiments in mice and monkeys to help them understand what went wrong. They found that in both animals, the infused virus left the liver and reached high levels in the spleen, lymph nodes and bone marrow. Even within the liver, the virus tended to accumulate in the Kupffer cells, which interact with the immune system, rather than in the main kind of liver cell, hepatocytes-which were the intended targets.

At least one of these unintended hosts contributed towards inflammation. Spleen cells in mice treated with the modified adenovirus produced IL-6 within hours. "They were cranking out this protein even without us tickling them to do that," says Wilson. "Unfortunately, until we saw this reaction in the human, we didn't know what to focus on in the mouse or monkey." Wilson thinks that altering the viruses that deliver genes so they interact less with cells that release IL-6 and other immunostimulatory molecules could make therapy much safer. Following Wilson's talk, Woo urged his colleagues to take these lessons to heart: "We all need to learn a lot of science from this patient," he said.
New Scientist issue: 20 January 2001


New Scientist

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.