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

Abstract

The principal symptoms of Huntington's disease (HD), chorea, cognitive deficits, and psychiatric symptoms are associated with the massive loss of striatal and cortical projection neurons. As current drug therapies only partially alleviate symptoms, finding alternative treatments has become peremptory. Cell replacement using stem cells is a rapidly expanding field that offers such an alternative. In this review, we examine recent studies that use mesenchymal cells, as well as pluripotent, cell-derived products in animal models of HD. Additionally, we provide further electrophysiological characterization of a human neural stem cell line, ESI-017, which has already demonstrated disease-modifying properties in two mouse models of HD. Overall, the field of regenerative medicine represents a viable and promising avenue for the treatment of neurodegenerative disorders including HD.

Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease

“…Previous studies have reported that transplanting external cells might generate new neurons in animal models for HD 43 . For example, transplantation of hESC-derived DARPP32 + GABAergic neurons or human NSCs may improved motor functions 10,44 .…”

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum

“…Here we wished to comprehensively evaluate whether hNSCs could survive for extended periods of time, whether they could further differentiate, and whether they could functionally compensate for loss of connectivity and neuronal function, which has not yet been described in a genetic model of HD. GMP-grade ESI-017 hNSCs (Holley et al, 2018; Reidling et al, 2018) were acquired as frozen aliquots (UC Davis), thawed, and cultured without passaging using the same media reagents as in the GMP facility. Mice were dosed by intrastriatal stereotactic delivery of 100,000 hNSCs per hemisphere at 2.5 months of age.…”

“…Previously we demonstrated that hNSCs are viable and integrate into the host striatum in a severe model of HD, the R6/2 (Holley et al, 2018;Reidling et al, 2018). However, due to rapid progression of the phenotype in these mice, examination of transplanted hNSCs was limited by time, about 4-6 weeks after implantation.…”

“…The use of neural stem cells (NSCs) for the treatment of neurological disorders is in the early stages but there is already a wealth of information indicating that NSCs may offer a viable therapeutic avenue (El-Akabawy et al, 2012; Choi and Hong, 2017; Connor, 2018). We recently demonstrated that human (h)NSCs implanted in the striatum of R6/2 mice, a severe and rapidly progressing model of HD akin to juvenile HD (Mangiarini et al, 1996), survive, are functional, and improve a number of HD phenotypes (Holley et al, 2018; Reidling et al, 2018). Studies also included the long-lived full-length homozygous Q140 HD mouse model and we showed behavioral improvements and reduced aggregation; however, characterization of cells was limited due to low cell survival rate, perhaps caused by insufficient immunosuppression methods.…”

Huntington's disease: From basic science to therapeutics

“…Notably, most studies demonstrate clear benefits on HD symptoms with some showing a possible mechanism of action that includes the release of neurotrophic factors such as BDNF. Sandra M. Holley (University of California Los Angeles, UCLA), working in the Cepeda‐Levine laboratory, and associates at the University of California Davis (UCD) and at the University of California Irvine (UCI) review the use of stem cells in HD animal models (pp. 329–342).…”