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huntington [ÀÛ¼ºÀÏ : 2016-03-25 10:33:50 ]   
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Mice with Huntington's Disease Successfully Targeted by Human Stem Cells, UC Researchers Say ~


Huntington's disease, a fatal neurodegenerative disease, is characterized by

the progressive neuronal loss in the striatum, a brain area involved in

motor and behavioral control, followed by generalized brain atrophy.

Striatal neuron loss is responsible for some of the more serious

Huntington's symptoms, such as impaired movement control, cognitive decline,

and severe behavioral disorders. Brain-derived neurotrophic factor (BDNF),

found to be reduced in Huntington's post-mortem human brains, is a promising

lead candidate for treatment of the disease, as it has been shown to prevent

neuron death and to stimulate the growth and migration of brain cells in the

brains of mouse models.

Mesenchymal stem cells (MSCs) have been shown to be effective in delivering

BDNF to mouse brains because they are not rejected by the immune system, as

it may occur with viruses, and they are attracted to sites of injury,

releasing other factors that reduce inflammation and enhance connection

between neurons. However, the use of human MSCs in mouse models has been

hampered by mouse immune systems, which rejects these foreign cells.

Researchers were now able to overcome these setbacks, advancing the

potential of the BDNF/MSC platform for clinical applications.

 

The UC Davis team designed a system to immuno-suppress mouse models of

Huntington's disease to successfully test the efficacy of BDNF delivery by

human MSCs. First, researchers isolated MSCs from healthy human bone marrow

donors and engineered them to secrete elevated amounts of BDNF. The grown

population of MSCs was then injected into the brains of Huntington's mouse

models, who were then tested weekly for behavioral changes and degeneration.

Mice injected with MSCs, compared to those injected with a placebo, showed

significantly less anxiety, a hallmark characteristic of Huntington's. In

addition, mice treated with MSCs showed less degeneration in the striatum,

increased neuron growth activity, and an extended lifespan, by 15 percent,

when com pared with control mice.

 

These results are an important step for researchers to get U.S. Food and

Drug Administration approval to test the therapy's safety and efficacy in

human patients with the disease. "For the first time, human stem cells have

been successfully used as a platform to deliver brain-derived neurotrophic

factor (BDNF), the growth factor that shows great promise for treating

Huntington's disease," principal investigator Prof. Vicki Wheelock said in a

news release <http://www.ucdmc.ucdavis.edu/publish/news/newsroom/10872> .

"We must complete additional animal studies before we can apply for

regulatory approval to test this therapy in Huntington's patients, but the

results we've seen using the human cell products in mouse models of the

disease are very encouraging."

 

==========================

 

 

 

Subject Category: Cell Therapy

 

Human Mesenchymal Stem Cells Genetically Engineered to Overexpress  Brain-derived Neurotrophic Factor Improve Outcomes in Huntington's Disease  Mouse Models

 

http://www.nature.com/mt/journal/vaop/ncurrent/full/mt201612a.html

   

Abstract: Huntington's disease (HD) is a fatal degenerative autosomal

dominant neuropsychiatric disease that causes neuronal death and is

characterized by progressive striatal and then widespread brain atrophy.

Brain-derived neurotrophic factor (BDNF) is a lead candidate for the

treatment of HD, as it has been shown to prevent cell death and to stimulate

the growth and migration of new neurons in the brain in transgenic mouse

models. BDNF levels are reduced in HD postmortem human brain. Previous

studies have shown efficacy of mesenchymal stem/stromal cells (MSC)/BDNF

using murine MSCs, and the present study used human MSCs to advance the

therapeutic potential of the MSC/BDNF platform for clinical application.

Double-blinded studies were performed to examine the effects of

intrastriatally transplanted human MSC/BDNF on disease progression in two

strains of immune-suppressed HD transgenic mice: YAC128 and R6/2. MSC/BDNF

treatment decreased striatal atrophy in YAC128 mice. MSC/BDNF treatment also

significantly reduced anxiety as measured in the open-field assay. Both MSC

and MSC/BDNF treatments induced a significant increase in neurogenesis-like

activity in R6/2 mice. MSC/BDNF treatment also increased the mean lifespan

of the R6/2 mice. Our genetically modified MSC/BDNF cells set a precedent

for stem cell-based neurotherapeutics and could potentially be modified for

other neurodegenerative disorders such as amyotrophic lateral sclerosis,

Alzheimer's disease, and some forms of Parkinson's disease. These cells

provide a platform delivery system for future studies involving corrective

gene-editing strategies.

 

 

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