Gene therapy shouldn't be abandoned: Australian researcher

The US Food and Drug Administration (FDA) this week suspended about 30 gene-therapy trials in the US after another 'boy in a bubble' patient in a French gene-therapy trial developed leukaemia.

But Australian gene-therapy expert Assoc Prof Panos Ioannou, head of the cell and gene therapy unit at the Murdoch Children's Research Institute (MCRI) in Melbourne, said the setback did not mean gene therapy should be abandoned, or that it posed unacceptable risks.

Ioannou said many novel medical procedures went through a phase in which some patients may die or develop complications.

Both of the boys in the French trial who have developed leukaemia had been experimentally treated for severe combined immune deficiency (SCID), an inherited disorder involving a key immune-system gene on the X-chromosome.

The disorder leaves affected males without an immune system, and vulnerable to microbial infections, as well as to cancers that are normally detected by immune surveillance. Most boys with X-linked SCID survive less than a year, unless they are isolated in microbe-free plastic tents -- hence the term 'boy in the bubble'.

The 10 boys involved in the French study were treated last year with genetically engineered bone-marrow stem cells, the progenitors of the specialised lymphocytes and leucocytes that protect the body against infection. Researchers used a disarmed retrovirus to insert a functional gene into their bone marrow stem cells to repair the defect.

The other nine patients were living normal lives, and were in good health, until the French research team this week notified the FDA that a second patient had been diagnosed with leukaemia.

Both boys are still alive, and are being treated for leukaemia with chemotherapy -- the cure rate for such leukaemia is around 90 per cent.

Prof Bob Williamson, the MCRI's director, said, "It's a predictable story. The risks (of virally-based gene therapy) are acceptable in the context of young boys who are likely to die of a lethal genetic disorder, but it clearly rules out (virally-based) gene therapy for many other people who require gene therapy for non life-threatening disorders."

"Many of us are sceptical about viruses, because they have the potential to introduce serious problems, but other approaches appear more promising for most patients."

Ioannou observed that conventional therapies for genetic disorders also remained high-risk. For example, the death rate among people receiving bone-marrow transplants to cure the lethal haemoglobin defect thalassaemia was around 30 per cent, and even in conventional bone-marrow transplants, mortality approached 10 per cent.

Researchers had anticipated some patients might develop leukaemia, because it was not yet possible to select where in the patient's chromosomes a modified retrovirus could safely insert a new gene.

"It's more or less random," he said. "But it's not completely random, because recent research indicates the virus prefers to insert new genes in the vicinity of active genes."

That's not good news, Ioannou said, because it meant that new genes were more like to disrupt the activity of genes involved in cell growth and division, and DNA replication and repair. Any disruption of these key genes could turn cells cancerous.

Major setback

Although both boys are still alive, and the other eight patients are in good health, the setback to the French experiment is the worst since an 18-year-old male in the US, Jesse Gelsinger, died unexpectedly after an experimental gene-therapy procedure for a rare liver disorder.

In Gelsinger's case, the virus involved was not a retrovirus, but an adenivorus, which infects cells without inserting its genetic blueprint, and any transgene, into the cell's chromosomes.

Iaonnou said most gene therapy experiments today involved modified retroviruses and lentiviruses like the HIV virus that causes AIDS. These specialised viruses normally insert their genes into the host cell's chromosomes.

Geneticists first disarm the viruses by removing all genes that could make the virus infectious and hazardous, leaving only a basic package necessary for the virus to integrate itself , along with the therapeutic gene, in the patient's chromosomes.

"Personally, I am among the scientists who believe there are other risks that have not been properly assessed," Ioannou said.

Ioannou said there was also a risk that the modified virus would recombine with other viruses currently infecting the patient, creating a new virus that could infect other people -- with much broader consequences for human health.

There was also the risk of insertional virogenesis -- "The patient may be infected by other viruses at the time, and recombination could create a new virus capable of infecting other people.

Another risk, he said, was that of activating dormant retroviruses, acquired over tens of millions of years of mammalian evolution, that constitute a large fraction of the human genome.