UC San Diego
Human neural stem cell therapy in a primate model for Parkinson's disease
- Author(s): Wakeman, Dustin Robert
- et al.
Neural stem cells derived from various sources have shown considerable promise for the treatment of parkinsonian symptoms in a variety of animal models; however, the long- term potential of human neural stem cells to engraft, differentiate into dopamine neurons, and restore function in the dopamine-depleted non-human primate brain remains unknown. This dissertation describes a clinically relevant paradigm for transplantation of undifferentiated human fetal subventricular-zone derived NSC in the parkinsonian primate, including gene therapy enhancement with GDNF. Chapter 1 reviews literature regarding functional properties of NSC that make them a candidate for cellular transplantation in neurodegenerative disorders, the potent neurotrophic effects of GDNF, as well as the rationale for utilizing large animals to adequately test stem cell therapeutics. Chapter 2 describes a novel culturing system to overcome cellular senescence and efficiently expand large-scale human fetal NSC long-term without aberration. Included are clinically pertinent techniques to produce and deliver hfNSC into both the rodent and primate brain, as well as new advances in radiological tracking and imaging utilizing FDA-approved supra-magnetic iron-oxide particles. Chapter 3 demonstrates the first reported evidence that undifferentiated hfNSC differentiate into some TH-ir neurons and restore functional deficits in parkinsonian non-human primates. Normalization of dopamine -levels and nigrostriatal circuitry argue for neuroprotective effects of endogenous cells rather than direct cell replacement. To allow for morphological analysis of donor grafts, reporter hfNSC were created (Ch.2) for long-term studies. Chapter 4 presents a new paradigm in which hfNSC are homotopically transplanted concomitantly with striatal AAV-GDNF to enhance graft survival and promote axonal outgrowth. Transplanted cells engrafted for up to 11-months and differentiated extensively congruent with host circuitry, demonstrating for the first time that undifferentiated hfNSC retain developmentally relevant programs of differentiation and respond to host signals in the dopamine-depleted primate brain. Further, evidence supports the standing argument that fetal subventricular-zone derived NSC do not significantly differentiate into mature A9-subtype midbrain dopamine neurons in-vivo, even in a GDNF-rich environment. Chapter 5 discusses the significance of these findings to cellular transplantation in the adult CNS and the future application of stem cell transplantation with regards to Parkinson's disease