Mice with Huntington’s Disease Successfully Targeted by Human Stem Cells, Researchers Say

University of California at Davis researchers have, for the first time, successfully tested human stem cells (MSCs) as a delivery system for a key protein growth factor in mouse models of Huntington’s disease (HD), an important step for the development of novel therapies.

The research article, “Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington’s Disease Mouse Models,” was published in Molecular Therapy.

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 compared 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. “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.”