Stem cell derived monkey neural progenitor cells as a platform for translational research in Huntington's disease Open Access

Carter, Richard Lee (2014)

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Huntington's disease (HD) is a dominantly inherited, neurodegenerative disorder caused by the expansion of glutamine residues in the N-terminal region of the huntingtin (HTT) protein. The disease results in progressive neuronal loss, leading to motor, cognitive, and psychiatric impairment. HD is a fatal disorder for which there is no cure. Existing treatments are aimed at the alleviation of symptoms; however, therapies that slow or reverse disease progression have yet to be implemented. A major focus of HD research is directed towards understanding and modeling mechanisms contributing to the degeneration of neurons. Pluripotent cellular models have been explored as a powerful tool to understand disease related changes as neurons develop. Pluripotent cell models also show promise in providing opportunities for the discovery of novel therapies. Here we report the establishment of neural progenitor cell (NPC) lines derived from pluripotent stem cells (PSCs) of transgenic HD monkeys. NPCs are mutipotent, self-renewing neural precursors committed to the neuronal lineage. PSC derived monkey NPCs are capable to generate neurons upon in vitro neural differentiation, and following xenotransplantation into mice striatum. Additionally, we show that HD neural cells develop cellular features of HD, including the formation of nuclear inclusions, oligomeric mutant HTT aggregates, and increased apoptosis upon cell stress. These phenotypes are rescued by genetic suppression of HTT and pharmacological treatment, demonstrating the ability of our HD cell model to respond to therapeutic treatment. The development and reversal of HD associated phenotypes in neural cells from HD monkeys provides a unique non-human primate platform for modeling HD pathogenesis and evaluating therapeutics that could be assessed further in HD monkeys.

Table of Contents

Chapter 1: General Introduction

1.1 Huntington's disease

1.2 Cellular pathology of Huntington's disease

1.3 Pluripotent stem cells and neurological disease

1.4 Stem cell derived models of Huntington's disease

1.5 Stem cell based therapy for Huntington's disease

1.6 Study Proposal

Chapter 2: Derivation and characterization of neural cells from non-human primates

2.1 Abstract

2.2 Introduction

2.3 Material and Methods

2.4 Results

2.5 Discussion

Chapter 3: Huntington's disease monkey neural cells develop classic neuropathologic phenotypes

3.1 Abstract

3.2 Introduction

3.3 Material and Methods

3.4 Results

3.5 Discussion

Chapter 4: Reversal of Huntington's disease associated cellular phenotypes support role of in vitro model for therapeutic evaluation

4.1 Abstract

4.2 Introduction

4.3 Material and Methods

4.4 Results

4.5 Discussion

Chapter 5: Conclusions and future directions

5.1 Summary

5.2 Future directions

5.3 Conclusion


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