Huntington’s Disease (HD) is a heritable neurodegenerative disease characterized by significant neuron loss in the striatum, a region of the brain primarily involved in voluntary movement, followed by widespread neuron loss in other brain regions. More information on the basics of HD, including symptoms and genetics, is available here.
The causes of neuronal death in HD are still not fully understood, however postmortem brains of HD patients show reduced levels of brain-derived neurotrophic factor (BDNF), a protein which normally plays an important role in neuronal health. Previous studies have shown that mice that do not express BDNF have HD-like symptoms such as reduced striatal volume, and that BDNF can prevent cell death and stimulate the growth and migration of new neurons in mouse models of HD. Since neuronal death is a major cause of the symptoms of HD, BDNF’s potential to not only maintain neuronal health but also stimulate growth of new neurons has placed BDNF as a promising option for the treatment of HD.
Studies examining the viability of BDNF as a treatment for the underlying neuronal loss seen in HD have been limited by the speed with which BDNF degrades and the lack of effective delivery methods. However, one group found that mouse mesenchymal stem cells (MSCs) engineered to overexpress BDNF significantly slowed disease progression in mouse models. MSCs are a type of multipotent stem cell, meaning that they are able to give rise to many, but not all, types of cells in the body. In addition, MSCs are relatively easy to deliver, and typically secrete cytokines and growth factors in the body to promote cell growth and repair. Due to these functions, MSCs are often described as a sort of “cellular paramedic.”
MSCs are also considered a valuable treatment option due to their extensive safety profile, having been used in various animal models as well as in humans with minimal negative effects. Unlike most other cells, MSCs can be transferred between organisms with minimal rates of immune rejection, typically suppressing immune response and reducing inflammation, making them a good candidate for transplantation or injection.
Given the benefits of MSCs secreted factors, including but not limited to BDNF, their robust safety profile, and ease to engineer, UC Davis researchers expanded on previous studies by engineering human MSCs to overexpress BDNF and then transplanting the cells into mouse models of HD.
This study utilized two different HD mouse models:
YAC128: This model displays reduced striatal volume and a slow motor and behavioral decline, and was therefore used for behavioral and brain volume studies. This slower decline is a good analog for typical adult onset HD.
R6/2: This model presents with early onset and rapid progression of disease symptoms, and has a significantly reduced lifespan. This model is better suited for evaluating neurogenesis potential, the ability to form new neurons, and lifespan extension.
Immune privilege capacities of MSCs did not extend across species in this study. As a result, both YAC128 and R6/2 mice were immunosuppressed in order to slow clearance of implanted human MSCs from the brain. Both YAC128 and R6/2 mice were intrastriatally injected with vehicle (no treatment), MSC, or MSC/BDNF (MSCs secreting excess BDNF).
The YAC128 mice were injected at 8 ½ months of age followed by behavioral testing for 6 weeks and striatal volume measurement post-mortem at 10 months. R6/2 mice were injected at 7 weeks of age and euthanized at 10 weeks of age to measure neurogenesis. Survival was calculated using a statistical method known as a Kaplan-Meier estimator.
The goal of this study was to evaluate the efficacy of a combined cell and gene therapy strategy, in the form of MSC/BDNF, as a treatment for HD. This model of delivery provides both the beneficial effects of MSCs as well as BDNF supplementation.
A common psychiatric symptom of HD is anxiety, and can be tested in mice with a variety of behavioral tests. In this study, researchers found that YAC128 mice treated with MSC/BDNF exhibited lower levels of anxiety when compared to non-treated YAC128 mice.
YAC128 mice that were not treated exhibited a significant amount of striatal atrophy, ~11%, compared to normal, non-HD mice. YAC128 mice treated with just MSCs exhibited a protective effect against neuron death with only ~8.5% striatal atrophy. However, the protective effect was stronger in YAC128 mice treated with MSC/BDNF, which displayed only ~6% striatal atrophy in comparison to wild-type mice, a statistically insignificant difference, suggesting almost complete prevention of striatal atrophy with MSC/BDNF treatment. These results showed MSC only treatment and MSC/BDNF treatment to both be notably protective of neurons.
The benefits to behavior and striatal volumes shown in the YAC128 mice could be caused by a number of underlying mechanisms. One possibility is that MSC/BDNF treatment promotes neurogenesis, or the growth of new neurons, which in turn produces reduced striatal atrophy and lower anxiety levels. Using the R6/2 mouse model, researchers found that those that were treated with MSC or MSC/BDNF exhibited higher levels of doublecortin, a neuronal marker for immature neurons, suggesting increased levels of neurogenesis.
Lastly, researchers found that R6/2 mice treated with just MSCs exhibited ~10% increase in lifespan compared to non-treated R6/2 mice. Mice treated with MSC/BDNF showed ~15% increase in lifespan compared to their non-treated counterparts.
A number of clinical trials have shown that infusion of MSCs into patients is relatively safe and has the benefit of being immunoprivileged, meaning that they are not attacked by the immune system once in the body. It should be noted that although immune privilege between organisms has been observed, it was not in this study. Previous and ongoing studies are evaluating the safety and viability of MSC injection or implantation into the brain or spinal cord for treatment of stroke, TBI, spinal cord injury, and neurodegenerative disorders. Building off of the information UC Davis researchers have gained from their own and others’ positive results in mouse studies, the next step is a clinical trial in human patients. The proposed clinical trial would evaluate the safety of implantation of gene-modified, BDNF secreting, MSCs to treat HD in human patients (HD-CELL). This would largely recruit from an ongoing observational study, PRE-CELL, which has followed patients with HD for 12-18 months conducting physical and neurological examinations, written and verbal tests, and measurements of daily function ability.
In conclusion, this research group asserts that the robust safety record of MSCs in clinical settings, preclinical efficacy data, and a lack of other available treatments for HD patients indicate strong support for a MSC/BDNF treatment clinical trial. Though these results and studies are still young, and many years stand between research and a safe, effective, available treatment for HD, they do offer hope and indicate significant progress in the fields of stem cell medicine and HD research. More broadly, this strategy offers new potential avenues of research and treatment for other neurodegenerative diseases such as Alzheimer’s disease, ALS (amyotrophic lateral sclerosis), and Parkinson’s disease.
Pollock, Kari, et al. “Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in huntington’s disease mouse models.” Molecular Therapy (2016).
Wheelock, Vicki, et al. “PRE-CELL: Clinical and Novel Biomarker Measures of Disease Progression in a Lead-In-Observational Study for a Planned Phase 1 Trial of Genetically-Modified Mesenchymal Stem Cells Over-Expressing BDNF in Patients with Huntington’s Disease (S25. 004).” Neurology (2016).