Viral transfection of mesenchymal stem cells to overexpress brain-derived neurotrophic factor and nerve growth factor as potential therapies for reducing behavioral deficits in the YAC 128 mouse model of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and emotional dysfunction. HD is caused by polyglutamine expansion in the IT15 region of chromosome 4 leading to selective degeneration of the medium sized spiny neurons (MSSN) of the striatum. Instrastriatal infusions of trophic factors, such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), have been shown to attenuate deficits in HD animal models, but this method of delivery only allows for short-term delivery of trophic factors. Cellular delivery of these factors has been shown to lead to a reduction in behavioral deficits but graft rejection often occurs due the body's immune response.;The current study evaluated the use of mesenchymal stem cells (MSC), which are known to be hypo-immunogenic, as a means of trophic factor delivery with a lower risk of immune rejection. MSCs, harvested from mouse femurs, were virally transfected to overexpress either brain derived neurotrophic factor (BDNF) or nerve growth factor (NGF). These cells or a vehicle solution were transplanted into the striata of YAC 128 transgenic HD mice and littermate controls at 4 months and behavioral testing was carried out in order to determine the motor and cognitive effects of transplantation. Mice were sacrificed at 13 months for immunohistological examination.;YAC 128 mice that received virally transfected MSCs showed an attenuation of cognitive and motor deficits. YAC 128 mice that received MSCs virally transfected to overexpress BDNF tended to show the greatest amount of behavioral recovery in motor tasks whereas mice that received MSCs virally transfected to overexpress NGF performed better in cognitive tasks. Histological analysis revealed that YAC 128 mice that received BDNF transfected MSCs had sparing of MSSNs and larger striata compared to untreated YAC 128 mice.;These results indicate that the use of virally-transfected MSCs may create an environment within the striatum that potentially abates or slows the dysfunction and neurodegeneration observed in the YAC 128 mouse model of HD. Further research on the long-term safety and efficacy of this approach is needed before its potential clinical utility can be assessed.