A study published this month in Science Advances by
a team of researchers at Macquarie University's Dementia Research
Center showed their treatment could prevent seizures in mice by clearing
build‑ups of a protein in the brain.
Epilepsy
is the most common neurological disorder worldwide, affecting about 70
million people. Two-thirds of those with severe epilepsy can be treated
with traditional medications, but about a third of patients do not
benefit from any of the available treatments. In some cases, the
seizures worsen when treated with standard drugs.
Dravet
syndrome, which is caused by a genetic mutation and begins in infancy,
is one such form of severe epilepsy. It can result in as many as 40
seizures an hour, and is associated with serious developmental delays
and a high mortality rate.
Professor
Lars Ittner and his team have been studying the causes of neurological
diseases for many years, including extensive investigations into the
role played by the build-up of tau proteins.
One
of their recent studies found hyperexcitation of the neurons caused by
tau protein build-up is a key driver of the progression of Alzheimer's
disease.
Hyperexcited
neurons fire continuously instead of only when stimulated, and can
result in seizures, neural network dysfunction, and cognitive decline.
Having
identified this link with hyperexcitation, the team began looking at
diseases other than Alzheimer's in which hyperexcitation was a key
feature, including epilepsy.
Tau proteins: A delicate balance
The
build-up of hyperphosphorylated tau in the brain's microtubules has
been shown to be associated with a number of neurological diseases,
including various forms of dementia.
When
functioning correctly, the phosphorylation process provides a
fine-tuning function that allows proteins to communicate with each
other. In the right amount and location, phosphoryl is vital to
maintaining the brain's signaling pathways, but too much can have a
toxic effect.
When a protein molecule becomes
hyperphosphorylated, too much phosphoryl sticks to its surface,
altering its shape and impairing its ability to bind to and communicate
with other proteins. The phosphoryl acts as a lubricant, allowing the
molecules slip apart and float free, while also changing their secondary
structure in a such way that they aggregate.
Professor
Ittner likens this process to hair being washed down a drain. The drain
can cope with a few hairs, but as more and more build up, they clump
together with other detritus and eventually block the pipe.
In this case, the pipe is the human neuron. Once blocked it dies, and no treatment exists to regenerate neurons.
The
newly published research, led by Nicolle Morrey, a second year Ph.D.
student from Professor Ittner and Dr. Janet van Eersel's team, the
researchers have proved that in contrast, when tau is phosphorylated by
kinase p38y at a specific location on the genome, Threonine 205, it can
prevent excitotoxicity, and therefore seizures.
"We can harness p38y to work in our favor," Professor Ittner says.
"Recently, we designed a new gene therapy vector, and by introducing our new therapy to the brains of mice via this vector, we have been able to show we can increase production of p38y only where it is needed."
When
treated with the new gene therapy, mice with uncontrolled epilepsy had a
better chance of survival, as well as showing marked improvements in
behavior and brain activity.
"We
have tested this therapy extensively, and rigorous assessment by
independent labs has confirmed our results," Professor Ittner says.
"Our next step is to conduct more detailed pre-clinical evaluation in preparation for clinical trials.
"It
is showing tremendous promise as a treatment for acute neurological
conditions, and we hope to be able to offer it, initially to patients
with uncontrolled epilepsy, within the next five to seven years."
Supporting the development of gene therapies
Earlier
this year, Macquarie University created a new company, Celosia
Therapeutics, to turn this and other ground-breaking research into
commercially available medical treatments.
Launched
with more than $2 million in seed funding from Macquarie University,
Celosia Therapeutics has exclusive access to a portfolio of patents for
advanced gene therapies developed by scientists including Professor
Ittner and Professor of Neurobiology and Neurochemistry, Roger Chung,
both of whom are leaders in their fields.
Celosia
Therapeutics CEO Dr. Brenton Hamdorf says the company is in the
pre-clinical development phase for these promising candidate therapies
for uncontrolled epilepsy and Alzheimer's Disease, with others in the
pipeline.
"The
therapies we have in development all have the potential to be
life‑changing for people suffering from these devastating diseases," Dr.
Hamdorf says.
"Our
partnership with Macquarie University and the Macquarie Incubator is
key to bringing these treatments from the lab to the bedside. These and
other partnerships, provide us with vital access to critical research
capabilities, infrastructure, clinical expertise, and patients who are
waiting for these new treatment options.
"We're at an exciting point with this research, and we're looking forward to seeing these therapies made available to patients."