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Study on Human Gene Therapy

In 1990, a three-year-old Cleveland, Ohio, girl named Ashanthi DeSilva made history when doctors infused her with genes to produce an infection-fighting enzyme called ADA that she lacked.

A decade later, the ashes of Jesse Gelsinger were scattered on an Arizona mountaintop after the 18-year-old died of respiratory distress — essentially, his lungs shut down — after getting a massive dose of a modified cold virus intended to carry a gene to his cells.

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Somewhere in between, the promise of gene therapy has fallen short.

“This severe death in a relatively healthy individual makes us say that we have a lot more to learn,” says Philip Marsden, an associate medical professor at the University of Toronto who conducts research on the genetics of blood vessels. “Clearly, with the development of gene therapy vectors, we will have to slow down.”

Last week, it was reported that a clinical trial in Philadelphia, intended only to prove the treatment was safe, allowed haemophiliacs to greatly cut their ordinary treatment with synthetic blood-clotting drugs. Meanwhile, it was recently disclosed that James Dent, a Toronto brain cancer patient, died unexpectedly in April 1997, two days after beginning the second stage of gene therapy.

Gene therapy has always sounded simple and elegant.

Put a “healthy” gene inside a “harmless” virus, infuse a patient, and the virus will carry the gene into cells by infecting them.

How can it fail?

The answer is proving complicated. Much of the problem is caused by the viral vectors used to transport genes.

In order to make a virus harmless, two things must be done.

First, its toxic components must be stripped away. Second, it must be made “replication-incompetent,” so that it will not make billions of copies of itself, bursting cells apart and spreading throughout the body. Otherwise, the immune system will destroy the virus, along with the helpful gene it is transporting. “So you give the virus all you need but you leave out a couple of chapters of the book of how to live as a virus,” explains Marsden. If too much of the virus is removed, it will lose its native ability to enter cells to inject its DNA. No viral vector is perfect. Some are too small to transport the large genes that rectify some inherited disorders. The larger ones risk being recognized as foreign by the immune system and attacked.

In the 1980s, Frank Graham, a Canadian scientist, found one of the best viruses to transport genes, a variant of a cold virus known as an adeno-associated virus, or AAV. It is especially good at invading cells. However, critics say the genes carried by AAV do not become well established in the cell’s nucleus, so when the cell divides, the genetic traits carried into the cell by the virus become lost.

In DeSilva’s case, the researchers were not sure enough new ADA genes had reached her cells. Her doctors argue she has done better than patients who get only the standard treatment or weekly ADA injections. To play it safe, she still receives her weekly shot.

To overcome this hurdle, gene therapists have to expose patients to very large amounts of virus, in the hope that a maximum number of genes will reach their target. Some experts think this massive dose is what caused Gelsinger’s immune system to flare up. Doctors from the University of Pennsylvania — home of one of the best gene therapy programs in the world — infused him with close to a trillion particles of AAV. Within 12 hours, he spiked a fever of 40.3C. He suffered jaundice. At 24 hours he slipped into a coma. Soon his lungs grew stiff, his kidneys shut down, and he died. “Multiple organ system failures” is listed as the cause of death.

Soon after Gelsinger’s death, U.S. health officials learned of at least six other unreported deaths involving gene therapy. “This may cause some people to look a lot more closely at adverse events,” says Marsden. In the December edition of the journal Nature Medicine, English and Australian researchers reported that patients who received gene therapy — using AAV — for brain cancer, had chronic brain inflammation. While the therapy halted the tumour growth, the strong immune reaction caused swelling in the brain that can lead to brain damage.

Scientists are now looking at other vectors to transport the genes more effectively. Some seem promising, but none has gone past the clinical trial stage. Meanwhile, the spate of deaths has led to a halt in many new clinical trials.

“This [the brain inflammation studies] could pose an important stumbling block for the future use of gene therapy,” wrote the Canadian Medical Association Journal.

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Study on Human Gene Therapy. (2021, Mar 18). Retrieved August 1, 2021, from