Study Rationale:
By the time Parkinson’s disease (PD) symptoms appear, typically 60% of neurons in the substantia nigra and their axonal projections (nerve fibers) to the striatum have degenerated. Since targeted axonal outgrowth is limited in the central nervous system, our approach is it to a use tissue engineering strategy to directly restore substantia nigra neurons and their axonal projections to treat PD. We plan to assess the capabilities of novel micro-tissue engineering neural networks (micro-TENNs), which are preformed constructs consisting of replacement neurons and long axonal tracts, in a model of PD.
Hypothesis:
We hypothesize that micro-TENNs will simultaneously restore substantia nigra neurons and reestablish long-distance axonal pathways to the striatum in order to restore function in models having undergone PD-like neurodegeneration.
Study Design:
Next-generation micro-TENNs consisting of dopaminergic neurons and long unidirectional axonal projections will be characterized and optimize in vitro. Micro-TENNs will then be transplanted into a neurodegenerative PD model to assess constructs survival, synaptic integration, dopaminergic functionality and PD symptom impact. Finally, we will assess the feasibility of stem cell-derived dopaminergic micro-TENNs in vitro as a step towards “personalized constructs” and clinical translation.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If successful, this work will show the ability of our unique micro-tissue engineering strategy to physically reconstruct lost pathways and alleviate the symptoms of PD. Moreover, the proposed studies will engender the creation of a broadly applicable, clinically viable regenerative medicine treatment strategy for lost neuronal and axonal populations in neurodegenerative diseases.
Next Steps for Development:
Future work would validate and optimize micro-TENNs in a more complex pre-clinical model exhibiting features of the underlying synucleinopathy in PD. Similarly, micro-TENNs would be advanced into larger animal models under as a final pre-clinical validation prior to human clinical trials.