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I copy news articles pertaining to research, news and information for Parkinson's disease, Dementia, the Brain, Depression and Parkinson's with Dystonia. I also post about Fundraising for Parkinson's disease and events. I try to be up-to-date as possible. I have Parkinson's
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Thursday, May 25, 2017

Brain-penetrating nanoparticles restore neuron function

May 25, 2017



FUS-mediated delivery of GDNF-BPN to the striatum of PD rats leads to a significant increase in GDNF protein levels in the striatum. Courtesy: Nano Letters


Researchers at the University of Virginia and Johns Hopkins University School of Medicine in Baltimore have developed a new, non-invasive and non-toxic genetic therapeutic technique to restore dopaminergic neuron function in rats suffering from Parkinson’s disease. The technique, which makes use of magnetic-resonance-image-guided ultrasound and brain-penetrating nanoparticles, reverses neurodegeneration thanks to expression of the neurotrophic growth factor GDNF in motor-neuron pathways. A singe injection of the nanoparticles continues to act for at least 10 weeks.

Parkinson’s disease is a largely idiopathic neurodegenerative disorder that affects roughly 2% of the over-65 population. It is thought to cost more than $14 billion a year in the US alone and looks set to double as early as 2040. One of the main hallmarks of the disease is degeneration of the neurons responsible for producing the neurotransmitter dopamine. This produces progressive and debilitating motor-control deficits, including bradykinesia, rigidity and uncontrolled trembling. 
Current treatments for Parkinson’s include administering pharmaceutical dopamine or surgical therapies like deep-brain stimulation. While these can improve symptoms in early stages of the disease, they do not protect neurons and the disease continues to progress. What's more, late-stage patients often develop other motor symptoms as a side effect of long-term dopamine replacement. All in all, therapies that can slow or stop the neurodegenerative process are still lacking.

Gene therapy

Gene therapy could be a solution here, with neurotrophic factors like the glial cell-line neurotrophic factor (GDNF) showing particular promise. These factors protect neurons from degenerating further and even regenerate neurons, enhancing the amount of dopamine generated. Many gene-therapy clinical trials have been completed in recent years using genes that encode for neurotrophic factors like GDNF or its close relative neurturin (NTRN). However, therapeutic outcomes have unfortunately proved rather disappointing. 
Direct injection strategies to deliver genes into the brain appear to be safe, but they are of course invasive, so they are often not considered for early-stage patients. To complicate matters further, the blood–brain barrier (BBB) prevents nearly all molecules larger than about 400 Da in size from entering the brain. Although this problem can be overcome to some extent using viral vectors and nanoparticles with BBB-targeting ligands in large systemic doses, these can lead to serious side effects.

MR image-guided focused ultrasound

MR image-guided focused ultrasound (FUS) is emerging as a way to non-invasively open the BBB for delivering nanoparticles as large as 100 nm into specific parts of the brain. This technique works thanks to activated microbubbles exerting mechanical forces on the brain vessel wall, temporarily disrupting tight vessel junctions, so allowing the particles to pass through. The good thing is that the brain’s barrier restores within four to six hours. The method has been FDA-approved for use in patients with essential tremor, and clinical trials for other central nervous disorders are now under way too. 
The story does not end there. Once across the BBB, vectors must pass through a dense, nanoporous and negatively charged extracellular matrix that blocks nanoparticles and viruses thanks to both adhesive interactions and so-called steric obstruction. Researchers recently found, however, that particles smaller than 114 nm and densely coated with hydrophilic and neutrally charged polyethylene glycol can overcome this barrier and rapidly diffuse across the brain-vessel walls. Importantly, these “brain-penetrating particles” (BPNs) can be complexed into nanosized and stable gene vectors by incorporating them into colloids. 

FUS opens blood–brain barrier in a targeted region

Researchers led by Richard Price of the University of Virginia recently showed that FUS can be used to deliver BPNs loaded with plasmid-DNA into the rat brain in a targeted region. They have now found that they can deliver BPNs loaded with a GDNF gene-bearing plasmid to the striatum of rats suffering from Parkinson’s whose BBBs had been transiently opened in a specific area using MR image-guided FUS. 
“The blood–brain barrier is only opened where we apply the focused ultrasound,” explains Price. “In essence, we ‘paint’ the brain volume we wish to transfect with the ultrasound probe so brain-penetrating nanoparticles are only delivered in that specific region.”

Reversing motor-behaviour deficits

The enhanced GDNF protein causes the neurons to either stop degenerating or to regenerate, he told nanotechweb.org. This then allows the neurons to express dopamine, which reverses the motor-behaviour deficits associated with the disease.
The study could open the way to using minimally invasive MR image-guided focused ultrasound to treat the underlying causes of Parkinson’s through gene therapy, he adds. The same general concept could be applied to treating brain tumours, for example, as well as other pathologies of the central nervous system.
The researchers, reporting their work in Nano Letters, say that they will now begin a set of additional experiments that will help them understand how best to translate their approach to clinical trials. “The second step is to test alternative therapeutic genes in the context of more sophisticated Parkinson’s models to potentially identify other approaches that may also be efficient when used with our delivery methods.”
http://nanotechweb.org/cws/article/tech/68870

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