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Genetic patch - exon skipping

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Postby rath » Fri Apr 23, 2010 1:18 pm


Researchers in Perth, Australia have developed a new kind of medicine that’s offering hope for people with serious illnesses. Different to genetic engineering, the technique works like a genetic patch, which fills in for defective genes when a cell divides.


Professor Steve Wilton
This is the ultimate personalised medicine. This could be huge.

Lesley Murphy
It’s actually extremely exciting from a personal point of view.

Professor Susan Fletcher
It really has opened the floodgates.

The enthusiasm is over a new kind of medicine, that helps correct genetic mistakes. It’s not genetic engineering, rather something quite ingenius: a patch to fill in for faulty genes.

Prof. Susan Fletcher
Ultimately most diseases have a genetic origin, even infections. I mean infections can be regarded as an acquired genetic disease.

Prof. Steve Wilton
This has enormous implications to a variety of conditions. Cancer, asthma, Alzheimer’s, diabetes.

But right now, the researchers are using their method for a much rarer genetic illness – a form of muscular dystrophy known as Duchenne. It’s a cruel disease. Conor Murphy was diagnosed at age three.

Lesley Murphy
Well there isn’t the words to describe what it’s like to be told that your child has got Duchenne. Your child has a condition which is untreatable, no cure. Nothing.

Conor Murphy
There’s days where you know you just don’t feel like getting up at all, like what’s the point kinda thing, but they don’t happen that often.

Lesley Murphy
It’s a pretty sad day when you come to realise that you wish your child had cancer. At least if they had cancer they’d be able to go to doctors' appointments, have therapies, have treatments, they still might not survive but you’ve got something, you’ve got hope.

Prof. Susan Fletcher
It’s an horrendous thing to be confronted with, families often go into shock and it affects the whole family. The disease is going to steal away his muscles, it's then going to steal his independence and then steal his life.

Part of the cruelty is nothing seems wrong in the beginning.

Prof. Steve Wilton
The boys look perfectly fine to start with. They have muscle damage, but the repairers of the young muscle keeps up with the degeneration. By the age of three to five years of age, parents start to notice the kids are a little bit slower than normal.

Prof. Susan Fletcher
The boys become weak. They lose the ability to walk by the age of 12, usually an electric wheelchair by maybe 12, 13, 14.

Prof. Steve Wilton
In the absence of good health care and maintenance, 90 per cent would be dead before they’re 20, they’re literally just too weak to breathe.

Lesley Murphy
And every day you grieve a little more, everyday your child loses the ability to do something else. It might only be a miniscule thing, but weekly, monthly, you see them deteriorating... dying, dying before your eyes and there is absolutely nothing you can do.

It’s usually males who get Duchenne, because the genetic mistake is on the X chromosome. Because females have two X chromosomes, they can normally compensate for the genetic error. The mistake is in just one gene.

Prof. Steve Wilton
The gene is called dystrophin and this is the largest gene in the human body, it really is an accident waiting to happen, it’s almost point one per cent of our genetic makeup.

An accident waiting to happen because the genetic machinery is so complex, a mistake in large genes occur from time to time.But remarkably, the Perth researchers have come up with a way to reprogram the body’s machinery, to work around the genetic mistake. It’s called exon skipping. And their work’s sufficiently advanced for the first human trials to begin in London. Sam Cornelius is in the trial. He’s 11 and hasn’t got to the wheel chair stage yet, but he has to endure painful stretching exercises every day.

Mrs Cornelius-Light
They’ve discovered that physio really helps this condition and that once the muscle has tightened, it's very difficult to get that muscle use back again. By keeping the muscles stretched every day it just stops them from tightening too quickly.

The trial was to see if the Perth scientists’ exon skipping treatment was safe and might have an effect.

Sam Cornelius - Light
They done a few blood tests first of all and they done a skin biopsy which hurt a little bit and then they put me to sleep and I had the injection put in my leg.

The medicine injected would act like a software patch.

Dr Graham Phillips
When there’s a defect in your computer’s operating system, a software patch is downloaded to fix it. Now wouldn’t it be wonderful if we could do something similar for defect in our genes. Well that’s just what’s being tested out here.

The problem for children with Duchenne is their gene error means a particular protein is not being made properly.

Prof. Steve Wilton
The gene acts to a code protein called dystrophi, which acts like a molecular shock absorber, giving strength and stability to muscle fibres.

Given muscle is involved in almost every body process, faulty dystrophin affects virtually everything. These scientifically accurate graphics show how the body’s dystrophin gene makes the protein. The gene’s corresponding stretch of DNA is read by the blue polymerase molecule shown here in blue. A copy of the information is made in the form of an RNA molecule. Unfortunately, the genetic mistake is copied too. The RNA, in turn, is read to make the protein.

Prof. Steve Wilton
Literally, it reads three letters at a time. These are called codons. It’s like a ticker tape machine. And these build up a protein. So you can see a protein being extruded.

But the genetic mistake means the dystrophin protein, shown here in red, is not built up properly. And that’s where the researchers’ ingenious software patch comes in. The patch is actually a small piece of the basic molecule DNA and RNA are made of nucleic acid. Using the chemical building blocks for nucleic acids, the scientists tailor make one to patch over the genetic mistake.

Dr Graham Phillips
This amazing machine can produce any piece of nucleic acid you want. All you do is enter in the letters – A G C – in the right order. It puts them together and produces the product.

Today, the Cornelius family have come to find out the results on the product injected into Sam. It’s early days yet, and this is a preliminary trial, but the message is positive.

Professor Francesco Muntoni
The results have shown that the children who received the height dose had also protein production. So they were able to produce some dystrophin.

Analysis of the patients’ muscle biopsies clearly showed new dystrophin protein had been made. Sam is now waiting for the next step: a full body infusion of the molecular patch to see if it can slow his deterioration.

Prof. Steve Wilton
Half the kids that were alive when I first started this work have now succumbed to their disease. I can’t afford to wait, I refuse to wait another 10 years for this therapy to get to more people.

Conor Murphy
It might not help me, I’m probably past the point of being able to walk again. But if it just gives me, you know, using my arms a bit more so I can scratch my head and take myself to the toilet or whatever, that way I won’t need many as much help as I get now. No point getting all annoyed and crying about it or whatever, because it’s not going to change anything. So you just get on with it.

Back in England, the next phase of trials for Sam should begin later this year. And in the coming years, as we find out more about the genetics of disease, the exon skipping technique could be used to treat a whole host of illnesses.


11 May 2009

RESEARCHERS at the Lung Institute of Western Australia (LIWA) have revealed a possible method to relieve symptoms of a debilitating muscle wasting disease, in a presentation at the recent 2009 LIWA Symposium.

Professor Steve Wilton presented “Splice manipulation as a therapy for Duchenne muscular dystrophy”, outlining exactly how exon skipping may be used to potentially reduce the severity of progressive muscle wasting.

Professor Steve Wilton, key speaker at the 2009 LIWA SymposiumDuchenne muscular dystrophy (DMD) is the most common and relentlessly progressive form of childhood muscle wasting, primarily targeting boys inheriting an X-linked recessive gene from their mother.

Caused by an absence of dystrophin, a protein that helps keep muscle cells intact, symptoms include weakness and muscle wasting, starting with the hips, pelvic area, thighs and shoulders.

It is one of nine types of muscular dystrophy, affecting voluntary muscles, on-setting in early childhood with sufferers as young as 2 years old.

Eventually all voluntary muscles are affected, including the heart and muscles used for breathing.

Survival is rare beyond 30 years old and there is no cure.

Professor Wilton says while better management of the disease has led to affected males living longer (due to physio, mechanically-assisted breathing and steroids), they are still restricted to a wheelchair before they are 12 years old.

“And parents are watching their boys go downhill in a highly predictable and progressive manner,” he says.

Professor Wilton’s presentation focused on the concept of exon skipping in order to interfere with dystrophin gene transcript processing, so that some parts can be removed from the gene message.

“The dystrophin protein acts like a molecular shock absorber for our muscles,” he says.

“One end binds to the cytoskeleton, the other binds to the sarcolema (muscle membrane).

“When a muscle fibre contracts or expands, the membrane and cytoskeleton move together in a coordinated fashion, but if you destroy this link, the membrane becomes more fragile and the muscle fibres are prone to damage.

“Repeated damage leads to loss of muscle and replacement with fat and fibrous tissue.

“Think of the flex in a garden hose providing strength and stability to the hose. If you had a hose with all the cross-linking broken, the hose will still work but will snap with a little wear and tear.”

“Duchenne MD is as bad as the disease gets and this is due to the dystrophin shock absorber being prematurely truncated and one end is missing.”

Professor Wilton says the milder form of the disease, known as Becker MD, involves in-frame deletions in the dystrophin gene.

“So you end up with a shorter shock absorber but the ends are still present and can still bind where it is supposed to,” he says.

“Depending upon where and how big the mutation is, some Becker MD patients can show little or no symptoms.”

In short, he says the research aims to “treat a DMD patient so the disease-causing part is snipped out so that we make a Becker-MD like gene transcript”.

To do this, the team will have to work out where the mutation is and then design an exon skipping strategy for that mutation.

“The first phase has been completed successfully where intramuscular injections of a compound restored dystrophin expression around the injection site,” says Professor Wilton.

“Work has been sent off for publication; however, results were so positive that the next phase, systemic treatment has begun.”

While the results provide hope, Professor Wilton says there is still much work to be done, firstly to ensure the compound is safe – which is especially difficult when trialling medications for children.

“The first systemic trials are unlikely to show any benefit, since very low doses must be used to show the compounds are safe,” Professor Wilton says.

“If there are no adverse events, the dose will gradually be increased. This will be a slow process.”

Professor Wilton says he estimates 70-80 percent of mutations will respond to exon skipping.
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