Explainer: Gene therapy offers cure for immune deficiency disorder in children

A cure for children with a severe immune deficiency disorder will be offered in Australia for the first time in a new cutting-edge gene therapy trial.

The disorder, called RAG-1 deficient Severe Combined Immunodeficiency (RAG-1 SCID), is caused by a genetic defect in the RAG-1 gene. Without treatment those born with the disorder will die within their first two years of life.

Children with SCID are born without infection-fighting B and T cells, and are extremely vulnerable to life-threatening infection as a result.

The gene therapy clinical trial has been broadened to include a trial site in Australia from the Leiden University Medical Centre (LUMC) in the Netherlands and will be led by the Murdoch Children’s Research Institute (MCRI) in Melbourne.

What is gene therapy?

Gene therapy uses genes to treat, prevent, or cure a disease or medical disorder.

Genes code all of the information about us, says Associate Professor Theresa Cole, a paediatric allergist immunologist at the Royal Children’s Hospital, and if you are born with a genetic disorder some of those genes might be abnormal.

“We have the capacity in the lab these days to be able to add in a functional copy of an abnormal gene that you’re carrying,” says Cole.

“We’re able to tag in an extra gene that’s able to provide normal function on top, of the abnormal gene, so, it overrides and corrects that problem.”

There are two main approaches to modifying a person’s genes in this way.

The clinical trial in those with RAG-1 SCID involves collecting stem cells from the children’s own bone marrow. These stem cells have had defective RAG-1 genes from birth, so the researchers introduce functional copies of RAG-1 into them.

Stem cells have the capacity to self-renew by dividing and to develop into more mature, specialised cells. 

Stem cells are sent to labs where the functional RAG-1 gene is introduced using a viral vector. Viruses have the innate ability to deliver genetic material straight into cells, so a virus that has been modified to no longer cause infectious disease can be used as a vehicle to carry therapeutic genes.

Then, the functional RAG-1 gene is picked up and read by the cell. The cells are then frozen, shipped back to the patient, and infused back into the body through the bloodstream.

The other main form of gene therapy involves introducing the new, functional gene straight into the cells of the body without having to remove stem cells first.

This involves introducing a viral vector directly into the body, through an injection for instance. A virus modified to no longer cause infectious disease can be used as a vehicle to carry therapeutic genes because some viruses have the innate ability to deliver genetic material straight into cells.

Gene therapy is primarily available in research settings although there are some specialised therapies commercially available in Europe and the US.

Gene therapy could provide a cure

Gene therapy has the potential to provide a life-long cure for children with RAG-1 SCID, while avoiding the complications associated with stem cell transplants used to treat it currently.

“When we do bone marrow transplants, we’re taking healthy stem cells from somebody else, not the patient’s own cells,” explains Cole.

“We match the donor to the patient… to make sure that the patient’s body is not going to recognise those cells as completely foreign. And those cells, when we put them in, also don’t recognise they’re in a completely foreign place.”

But that process has limitations, says Cole, and the biggest long-term problem is graft-versus-host disease. This is where transplanted cells start causing damage when they begin to recognise the body as foreign.

This can cause problems in various organs, like the gut, skin, and eyes, and theoretically anywhere in the body that those cells end up.

“That big group of complications that we worry about, that can have lifelong implications, are completely ameliorated if you use your own cells,” says Cole.

That’s not to say that, if identified early, children who have bone marrow transplants cannot do well. But the aim of this new gene therapy is for treatment to be even better.

“Our expectation is that we are fully correcting the immune system,” says Cole.

“And if you can correct your stem cells then they will, for the rest of your life for as far as we can foreseeably see, continue to produce functional immune cells.”