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13 Dec 2017

Issue 103, December 2008


The Nano-Neuro Initiative at University of Queensland Explores New Technologies for Huntington's Disease Treatments

Since the identification of the Huntington's Disease (HD) gene by Nancy Wexler and colleagues in 1993, the holy grail of researchers working in the field has been to develop an effective strategy with which to knockout the rogue protein (huntingtin) produced by the mutant gene.

Several significant hurdles face scientists in their attempts to effectively silence the huntingtin (HTT) protein, in the diseased neurons within the human HD brain. The first hurdle is the identification of a biological reagent that can specifically stop the production of the HTT protein without damaging normal cellular processes.

The second is to devise a non-toxic delivery system that can penetrate the defensive wall (the blood brain barrier) that protects the brain from toxic agents.

Thirdly, once past the blood brain barrier, these reagents must be able to enter the neuron. Neurons are known to be notoriously resilient to the uptake of biological reagents such as DNAs and RNAs.

Two new technologies have now become available that, when combined, may overcome these hurdles, Associate Professor Helen Cooper and Professor Perry Bartlett at the Queensland Brain Institute (QBI) have teamed up with Professor Max Lu and Dr Gordon Xu at the Australian Institute for Bioengineering and Nanotechnology (AIBN) at The University of Queensland (UQ) to exploit these new technologies.

In order to devise an effective strategy to knock down the production of the HTT protein in HD neurons, this UQ team has initiated a research program entitled "Novel hybrid inorganic nanoparticles for effective siRNA delivery to neurons".

The novelty of this project lies in the innovative approach of marrying two powerful technologies:

(i) RNA interference to silence the HD gene by stopping HTT protein production, and

(ii) Nanoparticle technology to create a delivery system that will be able to carry the interfering RNAs across the blood brain barrier and into affected neurons.

In 2007 the Australian Research Council (one of Australia's leading scientific research funding organisations) recognised the HD Nano Project's potential, allocating the research project a prestigious five-year development grant.

RNA interference
Over the recent years the process of RNA interference has emerged as a promising tool with which to prevent the production of unwanted proteins. Indeed, interest in RNA1 as a potentially powerful new class of pharmaceutical drugs is growing exponentially.

The importance of this technology has recently been recognised by the awarding of the 1998 Nobel Prize for Physiology or Medicine to Fire and Mello who first showed that small inhibitory RNAs (siRNAs) can prevent the production of targeted proteins. In the context of Huntington's Disease, the tough challenge for this technology is to deliver these siRNAs across blood brain barrier and into neurons.

The QBI/AIBN team believe that the answer to this problem may be to utilise nanoparticle technology to create a nanocapsule that will act like a "Trojan horse", to penetrate the blood brain barrier and then the neuronal membrane. An added bonus to this Trojan horse strategy is that the delicate siRNAs will be protected from the body's immune and other protective systems.

Progress in the Nano Lab
Nanotechnology is an applied science, which focuses on design, synthesis, characterisation and application of materials and devices at the nanoscale. The nanoscale dimension is 0.000,000,001, or one in one billion.

Prof Lu and colleagues have generated nanoparticles that exist as multiple layers of metal ions which have the capacity to adsorb small molecules such as siRNAs between the layers. The beauty of this arrangement is that the integrated molecules are protected from the external environment - an important property if siRNAs are to be delivered to neurons without being degraded when in the blood stream. Currently the AIBN scientists are defining and refining the physical properties of these high-tech compounds to ensure that they are safe and effective Trojan horses.

Success in the Neuro Lab
Within the QBI Neuro lab, a talented PhD student, Yunyi Wong, has now convincingly demonstrated that nanocapsules can indeed shuttle siRNAs into cultured mouse neurons. Excitingly, she has also be able to knockdown the levels of target proteins using the mouse neuron model.en

The Neuro team is now gearing up to test these nano-siRNA compounds in a mouse model of Huntington's Disease. Professor Lu believes that his team will be able to design specially shaped nanocapsules which will be able to pass unhindered through the blood brain barrier.

It is important to emphasise that this is an emerging technology. While all current results from the Nano-Neuro project indicate great potential, there is still a long way to go before it can be translated into the clinic.

The UQ scientists, however, believe that their research may lead to a therapeutic strategy in which nanoparticle-encapsulated siRNAs can be safely delivered on a routine basis to HD patients to continually suppress the production of the HTT protein.

While this potential treatment will not remove the mutant HD gene, the UQ Nano-Neuro team is hopeful that it will suppress the symptoms of HD, resulting in a significant improvement in the quality of life.

Helen Cooper
Queensland Brain Institute, The University of Queensland

Acknowledgement: Newsletter AHDA (QLD) Inc

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