New Bionomics mouse model shows epilepsy writ small
Wednesday, 03 December, 2003
When Florey Institute epilepsy researcher Dr Steve Petrou showed the electroencephalogram trace to his colleague, Prof Sam Berkovic, the veteran clinician recognised it immediately.
For Berkovic, director of the Epilepsy Research Institute in the Melbourne suburb of Heidelberg, the distinctive 3-Hertz spiking in the brain's electrical activity was the giveaway: the signature of a brain rendered temporarily oblivious to sensory input. It told him the patient suffered from absence epilepsy, and the EEG had caught him/her in the throes of a petit mal seizure.
Berkovic's diagnosis was spot-on. But he was stunned when Petrou told him the EEG was not from a human brain. It was from a transgenic mouse, carrying a mutation identical to the one that causes absence epilepsy in humans.
Petrou's mouse is the Mark II version of the world's first animal model of an inherited human epilepsy.
Berkovic and his colleagues conducted the pedigree investigation and clinical studies in families that allowed Prof Grant Sutherland's group at the Adelaide Women's and Children's Hospital to identify and clone the gene. Petrou then used a knock-in mutation to replicate the genetic defect in a laboratory mouse strain.
The Mark II mouse, like its progenitor, carries the same three-base deletion in a gene for one of the five subunits -- the gamma sub-unit -- that collectively form neuronal receptors for the excitatory neurotransmitter gamma-amino butyric acid (GABA).
Petrou is a vice-president of Adelaide biotechnology company Bionomics (ASX:BNO, US OTC:BMICY), Bionomics, which has previously filed patents for the Mark I mouse, announced this week it has filed patents on its new, Mark II murine model of human epilepsy.
Bionomics CEO Dr Deborah Rathjen said that although the original transgenic mouse has the same mutation as families affected by the disorder, and spontaneously develops epileptic seizures, it does replicate the symptoms of typical absence-epilepsy seizure in humans: immobilisation, an unseeing gaze, and rhythmic 3Hz spiking on an EEG.
Instead, the mice exhibited tonic-clonic symptoms typical of grand mal seizures in humans: body rigidity, rhythmic muscle spasms, and loss of consciousness.
Petrou crossed his original mouse with a different inbred strain to produce the Mark II mouse --a murine replica of human absence-epilepsy, right down to the EEG trace.
Introducing the absence-epilepsy mutation into a different genetic background did the trick, and in the process provided strong support for Berkovic's 'digenic' model of inherited epilepsies.
Hereditary epilepsies are clinically complex disorders -- even where the primary mutation has been well characterised, members of multi-generational families carrying the same mutation often exhibit very different symptoms.
'Epilepsy genes'
Around a dozen 'epilepsy genes' have now been identified, most of them by Bionomics and its academic collaborators. Nearly all are ion-channel genes, which propagate signals through the brain's neural networks by modulating the flux of calcium, sodium and potassium ions through nerve-cell membranes.
Berkovic describes inherited forms of epilepsy as "channelopathies" that cause neurons to fire abnormally.
His digenic model proposes that variable symptoms of inherited epilepsies arise in interactions between a primary mutation in an ion-channel gene, and particular variants (alleles) of other unidentified genes. Some may be normal alleles of the same gene, or other ion-channel genes.
Because every family member inherits a unique mix of their parents' genes, there is potential for a variety of interactions, and a diverse spectrum of symptoms.
Petrou found that only 5 per cent of mice carrying one copy of the mutant GABA-receptor gene developed epilepsy; all mice with two copies of the gene were affected.
Rathjen said Bionomics planned to license other research agencies and companies to use the absence-epilepsy mouse in research, under collaborative research arrangements.
The Bionomics mouse was developed with the help of a National Institutes of Health research grant. "The NIH is encouraging the development of animal models for specific types of epilepsy, and there has previously been no model of absence epilepsy," she said.
Rathjen said the mouse would allow researchers to test the effect of current and prospective anti-epileptic drugs, and an improved ability to identify drugs that are more likely to be effective in treating patients with absence epilepsy. Around 30 per cent of patients with absence epilepsy do not obtain adequate control with existing drugs.
Bionomics says 2 million of the estimated 7 million people in developed nations who suffer from epilepsy are inadequately treated; the estimated global market for epilepsy drugs is around $US6 billion.
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