What weve dreamed about for several decades now is becoming reality, says Professor Ian Alexander, head of the gene therapy research unit at the Childrens Medical Research Institute. We are about to see a big rush of these therapies coming into the clinic. Its really started screaming upwards in the last few years its exponential.

We stand on the very tip of the iceberg. The first gene therapy was approved in China in 2004; over the next 10 years, global regulators approved just four more. In just the past 18 months, regulators have approved five treatments with two more awaiting final approval and another 3633 therapies in the pipeline, according to tracking by the American Society of Gene and Cell Therapy.

Were at the stage where there is a huge bulge coming down the clinical trial pipeline. Its almost exceeding capacity, says Dr Thomas Edwards, head of retinal gene therapy research at the Centre for Eye Research Australia. Its an exciting time for patients, it wasnt long ago we had nothing for them.

Many of the drugs we have, such as penicillin or Tamiflu, work by killing bacteria or viruses. Vaccination uses a dead virus to prime the immune system. Synthetic hormones like insulin treat the bodys own shortages. Chemicals in pill form, such as selective serotonin reuptake inhibitors, float through the bloodstream, enter our cells and change our chemistry.

Gene therapy is different. Rather than alter our chemistry, it treats us by changing our genotype, the way our DNA is expressed.

It is a new paradigm. It offers the first possibility of curing diseases at their root genetic cause and the possibility of a lifelong cure, says Rasko. And we are seeing that now in patients.

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Understanding Zolgensma gives you an idea of how different this new medical era will be.

Every time you go to scroll an article or turn the page in a newspaper, your brain converts that thought to a signal. It runs down your spinal cord to motor neurons, cells that reside in the cord but project thin tendrils out into the flesh. These tendrils called axons carry commands from neuron to muscle.

Like every cell in your body, each motor neuron carries a full copy of your genome, separated across 23 pairs of chromosomes and locked tight in the cells nucleus.

On chromosome five is a short stretch of genetic code known as SMN1. This gene is a blueprint for a protein crucial to the motor neurons function.

SMN1 is in an unfortunate place. The stretch of chromosome it lies in is prone to errors. Make a coding error in SMN1 and you blur the blueprint. The motor neurons struggle to build their crucial protein and soon start dying.

Without motor neurons, the signals from the brain to eat, to move, even to breathe stop getting through. In about 1 in every 10,000 babies born in Australia every year, this gene has an error.

Zolgensma, marketed by Novartis, comes in a small syringe, just 50 milliltres. Inside the syringe, in fluid, is a genetically-modified adeno-associated virus, the organic machines that make the treatment possible.

As far as science can tell, AAVs are harmless to humans. They infect us without us ever knowing. Scientists slice out the part of the viruss genetic code and replace it with a copy of SMN1. Inside the body, it crosses from the blood to the spinal cord and quickly infects motor neuron cells. Its the perfect vehicle, says Associate Professor Michelle Farrar, a paediatric neurologist who led a clinical trial of the drug at Sydney Childrens Hospitals Network.

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The virus enters the nucleus the vault where DNA is kept and releases its copy of the SMN1 gene. Unlike Gattaca-style genetic editing, the new gene is not incorporated into the patients DNA but floats nearby. Extra genetic code attached to the gene instructs the cell to activate it and start churning out copies of the key protein the motor neurons need.

Unlike most cells in the body, motor neurons dont divide; youre born with all you have. This is why losing them is so dangerous but it also means that if you can repair the faulty gene, you should have a therapy that works long-term. Some patients are now eight years post-treatment with no sign its wearing off, says Farrar.

Zolgensma does come with risks: serious liver injury or failure. Two patients on one of the drugs key clinical trials had signs of liver damage; a third had swelling on the brain requiring surgery.

Indeed, liver damage remains a problem with many gene treatments, with multiple deaths reported in clinical trials.

It remains unclear why. But the therapies rely on treating one disease by essentially infecting a patient with a benign virus, and when you put something in the blood a lot of it is going to end filtered out by the liver. One theory: in some people the immune system might spot and attack the build-up of virus in the liver, leading to extreme systemic inflammation and death.

Safety concerns have dogged gene therapy ever since the death of Jesse Gelsinger the young man who, in 1999, became the face of the treatments limitations after he died while participating in a clinical trial.

His death was a very sobering experience for the field, says Alexander from the Childrens Medical Research Institute a sign that scientists understood far less than they thought. There was a mismatch between the technology and the understanding.

Rasko is tougher on his colleagues. In 1999, when Jesse passed, essentially the whole field stunk. Everyone was accused of overhyping, and no one was delivering.

In response, the field curtailed its ambition and pivoted toward diseases that are a better match for the quickly developing technology.

Early treatments were held up because of the struggle to deliver enough of the gene without provoking a huge immune response. By switching to adeno-associated viruses small viruses that infect humans and some other primate species scientists found they could deliver more genetic code while reducing the immune response. And the field started hunting for conditions that seemed a better match for gene therapy.

Zolgensma and Spark Therapeutics Luxturna, approved for government subsidy in March, both use the same adeno-associated virus to target cells that are easy to access and do not divide.

Luxturna treats a genetic cause of blindness by supplying a replacement copy of a defective gene to cells in the retina, allowing them to make a protein crucial for sight.

The gene is small and easy to package in the virus. And the eye, you can get at it relatively easy surgically, says Eye Research Australias Edwards. And [the retina] has immune-privilege the virus does not cause a widespread immune reaction.

Both Zolgensma and Luxturna are extraordinarily expensive, raising the question of whether gene therapy will be a medicine of the rich. Experts are hopeful that wont be the case.

Some of the early therapies will be for small groups, but eventually a gene therapy that can be used by many people will come online, says Professor Robyn Jamieson, head of the eye genetics research unit at the Childrens Medical Research Institute. Those economies of scale will push the price down for everyone.

And now the technology has been proven to work, competition among biotechs to develop new therapies is fierce. They are jaw-droppingly expensive now, says Rasko, but over time that competition should pull costs down.

And new facilities to make the viral machines at the heart of the treatment will also come online. This year NSW invested $25 million in a pilot factory to make viral vectors in Westmead.

None of this can come quickly enough for the hundreds of thousands of families across Australia living with genetic illnesses.

Shes very stubborn, very strong-willed, Adriana Baron says of her daughter, Mariana. And that helped her.Credit:Simon Schluter

To get Mariana the treatment she needed, Adriana had to battle first to get a diagnosis, then get approved for the treatment, and then get government funding to bring it into the country. But shes a fighter, just like her daughter.

Shes very stubborn, very strong-willed. And that helped her, says Adriana. If she wants to do things on her own, she tells you, I dont need any help, she does it herself.

Liam Mannixs Examine newsletter explains and analyses science with a rigorous focus on the evidence. Sign up to get it each week.

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A new era: After winding path and safety scares, gene therapy enters the clinic - Sydney Morning Herald