Finding cures for children's genetic diseases


One step closer to helping cure genetic diseases

Scientists at Children’s Medical Research Institute (CMRI) have made an important discovery published in Nature Genetics that will make gene therapy--which is already helping to cure genetic diseases—safer and more effective for children like Charlize Gravina.

Two-year-old Charlize, and her twin brother, Isaac, were both born with a rare and severe metabolic disease called Propionic Acidemia. Children with Propionic Acidemia have trouble breaking down and using amino acids from food, causing problems with appetite, low muscle tone, low platelets and white blood cells. They are missing a vital enzyme which causes toxic and harmful substances such as ammonia and propionic acid to build up in their blood.  If the illness cannot be controlled they go into a metabolic crisis which can cause breathing problems, seizures, swelling of the brain, stroke and coma leading to death.

“Initially, we were relieved to finally have a diagnosis.” A diagnosis meant Isaac & Charlize could be transferred to a specialist hospital, The Children’s Hospital at Westmead (part of the Sydney Children’s Hospitals Network), where they could receive the treatment that they so desperately needed before it was too late. “Once we were told by the Senior Staff Specialist Metabolic Doctor what the disease was and how it would affect our babies, we were completely crushed. We were absolutely devastated that our brand new beautiful twins would not have the normal life that we had imagined for them and that they deserved,” Julie said.

Isaac underwent surgery for a new liver, which is supposed to make enough of their missing enzyme to help them have a much more normal life. But after surgery, he had a mass bacterial infection and went into septic shock. Sadly, on 23rd January this year, Isaac passed away. Now his twin sister, Charlize, is on the transplant list as she awaits a new liver.

“We look forward to a future where gene therapy would be available to completely cure our beautiful daughter Charlize and children like her living with the most severe metabolic diseases,” Julie said. “We just wish that future was now so we wouldn’t have to expose Charlize to those same risks associated with organ transplant that ultimately took our precious boy.”

Gene therapy is already helping patients internationally overcome genetic diseases like haemophilia. But gene therapy treatments still need to be tailored to the thousands of conditions where this approach offers the prospect of effective treatment. A lot of work remains.

Central to this work, in key organs such as the liver, are the gene transfer tools used to replace or repair faulty disease-causing genes—AAV vectors. AAV vectors are like miniature Trojan horses that are used to carry healthy copies of genes into cells and even microscopic repair kits that can fix errors in DNA.

These vectors are safe because they are derived from a naturally occurring AAV virus. “Up to 70% of people have been exposed to naturally occurring AAV already and suffer no ill effects,” said Professor Ian Alexander, Head of the Gene Therapy Research Unit, a joint initiative of CMRI and The Children’s Hospital at Westmead.
But when giving gene therapy to children, safety is a top concern. Professor Alexander and his team have identified a small region in naturally occurring AAV that can sometimes have negative effects on liver cells.
“Knowing what this region of AAV does, provides us with a new way of measuring the small risk associated with gene therapy in the liver, and will allow us to more accurately balance risk against likely benefits. “

What’s more, the discovery by Professor Alexander and his team will help improve gene therapy going forward. “Now we’ve identified this element, we can edit it out of our AAV vectors, which is important when clinicians want to treat brain diseases but not affect the liver, for example. This means increased specificity as well as safety.”
Prof Alexander’s work is the result of a collaborative research effort within Paediatrio™, a co-operative joint venture between Sydney Children’s Hospitals Network, Children’s Medical Research Institute, and Children’s Cancer Institute.

There are currently a 130 registered AAV clinical trials globally, with over 2000 patients treated, so far and this will only grow in the future. Professor Alexander’s work will help ensure that research produces safe as well as effective cures for genetic diseases. And the sooner such treatments are available for children, like Charlize, the better.