Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice

Abstract

SummaryHuntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies.

Therapeutic effects of stem cells in rodent models of Huntington's disease: Review and electrophysiological findings

“…In addition, R6/2 mice implanted with hNSCs showed a statistically significant improvement in rotarod performance and the pole test. Neuromuscular function (grip test) and motor coordination also were significantly improved 4 weeks after implant . In this publication, it was shown that mice treated with ESI‐017 hNSCs in the striatum exhibited a significant change in some of the electrophysiological alterations seen in MSNs.…”

“…In a different study, when rats were implanted with hNSCs (fetal‐derived) prior to receiving 3‐NP administration, motor performance was enhanced compared to rats that received stem cells after 3‐NP administration or those that received vehicle only . A recent study by Reidling et al is the first report illustrating the therapeutic benefits of a human ESC‐derived NSC line in two mouse models of HD, the R6/2 and the CAG140. In both models, hNSCs were implanted during the presymptomatic stage, supporting the idea that the time of implantation may influence therapeutic outcomes.…”

“…Of those lines, four (including ESI‐017) were chosen for the generation of GMP and Good Laboratory Practice‐grade hESC banks for preclinical research based on the absence of human and nonhuman pathogens . Subsequently, an hNSC line was differentiated from the GMP‐grade hESC line ESI‐017 . ESI‐017 hNSCs stain for CD24, SOX1, Nestin, and Pax6 hNSC markers, as well as the proliferation marker SOX2, but do not stain for the pluripotent marker SSEA4.…”

“…At this stage, R6/2 mice were fully symptomatic. Details for electrophysiological recordings in ex vivo brain slices have been published …”

“…In this review, we present recent advances in the use of various stem cell types in animal models of HD. In addition, we provide further electrophysiological characterization of ESI‐017 human neural stem cells (hNSCs), a good manufacturing practice (GMP)‐grade cell line which has already shown promising results in two HD mouse models . Before reviewing the use of stem cells in HD research, we will briefly describe the animal models used in these studies.…”