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

Huntington'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.

Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease.

BACKGROUND: No disease modifying treatment currently exists for Huntington's disease (HD), a fatal neurodegenerative disorder characterized by the formation of amyloid-like aggregates of the mutated huntingtin protein. Curcumin is a naturally occurring polyphenolic compound with Congo red-like amyloid binding properties and the ability to cross the blood brain barrier. CAG140 mice, a knock-in (KI) mouse model of HD, display abnormal aggregates of mutant huntingtin and striatal transcriptional deficits, as well as early motor, cognitive and affective abnormalities, many months prior to exhibiting spontaneous gait deficits, decreased striatal volume, and neuronal loss. We have examined the ability of life-long dietary curcumin to improve the early pathological phenotype of CAG140 mice. RESULTS: KI mice fed a curcumin-containing diet since conception showed decreased huntingtin aggregates and increased striatal DARPP-32 and D1 receptor mRNAs, as well as an amelioration of rearing deficits. However, similar to other antioxidants, curcumin impaired rotarod behavior in both WT and KI mice and climbing in WT mice. These behavioral effects were also noted in WT C57Bl/6 J mice exposed to the same curcumin regime as adults. However, neither locomotor function, behavioral despair, muscle strength or food utilization were affected by curcumin in this latter study. The clinical significance of curcumin's impairment of motor performance in mice remains unclear because curcumin has an excellent blood chemistry and adverse event safety profile, even in the elderly and in patients with Alzheimer's disease. CONCLUSION: Together with this clinical experience, the improvement in several transgene-dependent parameters by curcumin in our study supports a net beneficial effect of dietary curcumin in HD.

AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease.

We report the characterization of a new rapid-onset model of Huntington's disease (HD) generated by adeno-associated virus (AAV) vector-mediated gene transfer of N-terminal huntingtin (htt) constructs into the rat striatum. Expression of exon 1 of mutant htt containing 70 CAG repeats rapidly led to neuropathological features associated with HD. In addition, we report novel data relating to neuronal transduction of AAV vectors that modulated the phenotype observed in this model. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that AAV vector-mediated expression in the striatum increased by >100-fold as compared to the endogenous htt level. Moreover, AAV vectors exhibited nonuniform transduction patterns in striatal neuronal populations, as well as axonal transport leading to transduction and neuronal cell death in the globus pallidus and substantia nigra (SN). These findings may inform future studies that utilize AAV vectors for neurodegenerative disease modeling. Further, RNA interference (RNAi) of mutant htt expression mediated by virus vector delivery of short hairpin RNAs (shRNAs) ameliorates early-stage disease phenotypes in transgenic mouse models of HD. However, it has not been reported whether shRNA-mediated knockdown of mutant htt expression is neuroprotective. AAV-shRNA was shown to mediate a dramatic knockdown of HD70 expression, preventing striatal neurodegeneration and concomitant motor behavioral impairment. These results provide further support for the use of AAV vector-mediated RNAi as a therapeutic strategy for HD.