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

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.

Using Genome Engineering to Understand Huntington’s Disease

“…This technique has yet to be tried in Huntington model mice; however, previous studies have used ATFs to repress transcription in the brains of mice (Bailus et al 2016). Another approach using CRISPR would involve increasing transcription of genes that could be neuroprotective in HD; BDNF could be a potential target for this type of therapy (Pollock et al 2016). As screening studies are further refined using more genetically engineered isogenic cell lines, it will be possible to uncover additional gene regulation targets.…”

Engineered BDNF producing cells as a potential treatment for neurologic disease

“…[89] Overexpression of BDNF using mesenchymal stem cells (MSCs) in HD mouse models have shown amelioration of behavioral deficits in HD mouse models,[90] increased striatal volume and neurogenesis. [12]…”

“…[12] These cells were prepared in a clinically compliant manner, mimicking cells proposed for a Phase I clinical trial. The YAC128 and R6/2 transgenic HD mouse models were used for behavioral and histological studies following transplantation to measure efficacy of MSC/BDNF as a putative therapy for HD.…”

“…Studies have shown that MSCs do not permanently engraft into host tissues; however, the duration and strategic localization of BDNF production should be adequate to produce a beneficial effect that will outlast the survival of MSCs. [12,103]…”

“…BDNF is of potential interest due to the widespread prevalence of TrkB, BDNF’s preferential receptor in the central nervous system (CNS), and its role in potentiating neuronal cell fate through various canonical signaling cascades [5] that influence survival, neuronal outgrowth,[6,7] and plasticity. [8] Loss of BDNF has been implicated in a number of neurodegenerative diseases,[9] while restoration or addition of exogenous BDNF has shown a physiologic therapeutic effect [10–12] (Figure 1). …”