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Silencing Parkinson's Disease

June 09, 2015

Silencing Parkinson's Disease

Actor Michael J. Fox has it. So do boxing legend Mohammad Ali, pop singer Linda Ronstadt, and evangelist Billy Graham. They are among the estimated 5 to 10 million people around the world suffering from Parkinson’s disease (PD) (Reference: 10 Famous People With Parkinson's Disease, Everyday Health; See also Statistics on Parkinson's, Parkinson's Disease Foundation). It is a progressive, non-curable neurodegenerative disorder triggered by neurons in the brain that gradually break down or die. PD's underlying causes are unknown. Researchers suspect genetics, environmental factors, and microscopic clumps of proteins inside brain cells called Lewy bodies (named after their discoverer Frederic Lewy) are to blame. What is known is that PD affects its sufferers differently, leading some to call it a “boutique disease.”

There is nothing posh about PD symptoms. The most common are motor skill issues, from tremors to balance and coordination problems. Others experience speech and swallowing issues, or dyskinesia, the involuntary flailing or jerking movements that can result from long-term use of levodopa, the most common Parkinson’s disease medication. Still more sufferers are unable to walk or even stand. As the disease progresses, some patients experience dementia and a rash of other symptoms, such as difficulty swallowing, that can even result in death (Reference: Parkinson's Disease Causes, Mayo Clinic; See also Parkinson's Disease Prognosis, The Michael J. Fox Foundation For Parkinson's Research).

Natural-born Killers

Scientists have been studying the PD scourge for centuries. While a cure remains elusive, a number of treatments have evolved and researchers are now tantalizingly close to understanding – and in some instances even controlling – what triggers the disease in the brain (Reference: Caspases: the executioners of apoptosis, Biochem J).

It begins with the activation of caspsase-3, a member of the caspase family of proenzymes that plays an essential role in programmed cell death. Every day, these sleeping assassins are activated during the cell death process known as apoptosis to kill off billions of DNA-damaged, superfluous, or unwanted cells in our brains. In many respects, these mediators of programmed cell death play a vital role in normal brain development and help regulate molecules for immunity, cell division and differentiation, and cell fate determination. Unfortunately, these natural-born killers also figure prominently in the rise of PD (Reference: Ibid; See also Emerging roles of caspase-3 in apoptosis, Nature).

Silencing the Assassins with Nanoparticles

Many PD symptoms occur when brain cells that produce dopamine are damaged or destroyed by caspase-3 during the cell death process. Dopamine is a neurotransmitting chemical that acts as a messenger service to different parts of the brain that control movement. Loss of dopamine causes neurons to fire without normal control, leaving patients less able to direct and regulate their physical activities (Reference: Parkinson's Disease Causes, The Michael J. Fox Foundation For Parkinson's Research).

Scientists have been working for years on ways to silence caspase-3 in order to prevent the progress of various neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases (Reference: Caspases: the executioners of apoptosis, Biochem J; See also, Targeted imaging of activated caspase-3 in the central nervous system by a dual functional nano-device, Journal of Controlled Release; Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain-targeted nanoparticles in a rat model of Parkinson's disease, PLoS One). Initially, researchers needed to find a safe and efficient way to cross the semi-permeable blood-brain-barrier (BBB) using mice and rats, a standard procedure in all recognized preclinical research. The BBB allows some materials to cross over into the brain, but prevents others from doing so as a type of natural safety mechanism that protects the brain from foreign substances and helps to maintain a constant environ for the brain (Reference: The Blood Brain Barrier ("Keep Out"), Neuroscience For Kids, Eric H. Chudler, Ph.D., University of Washington).

Recently, researchers at Fudan University in Shanghai, China, successfully developed a brain-targeted gene delivery system that is linked to a rabies virus molecule. That system, or vector, is capable of passing through the BBB. The vector also carries a special nanoparticle payload that includes caspase-3 shRNA (shot hairpin ribonucleic acid), an artificial RNA molecule used to silence target gene expression, in this case caspase-3. In so doing, the nanoparticle inhibits the activation of capspase-3 and prevents the progress of Parkinson’s disease.

Does it work? In vivo imaging of the process using PerkinElmer's innovative IVIS® SpectrumCT pre-clinical imaging system clearly indicates that the targeted nanoparticles accumulate in the brain more efficiently that non-targeted nanoparticles. When administering multiple doses of the rabies virus-laced nanoparticles intravenously, they visibly reduced caspase-3 levels, helped to preserve dopaminergic neurons, and improved the locomotor abilities in rats.

A Collaboration To Advance Disease Treatment

As in all pre-clinical research, Fudan University’s success in developing targeted nanoparticles to fight Parkinson’s disease is a long way from human trials. Hopefully, that day will come sooner, thanks to an innovative colloboration. Recently, Fudan University and PerkinElmer launched a new center of excellence – The Fudan University Shanghai Medical College-PerkinElmer Joint Small Animal In Vivo Imaging Demonstration Lab. Outfitted with world's most advanced bio-imaging technology – including the IVIS® SpectrumCT – the 90-square-meter lab provides a state-of-the-art venue for ongoing collaboration into cell and animal research and someday may even help in finding a cure for neurodegenerative disorders such as Parkinson’s disease.

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