Promising Outcomes of Original Grant:
The classic motor deficits of Parkinson’s disease (PD) are caused by degeneration of dopamine neurons, resulting in the loss of part of the neurons called axonal projections that modulate a cluster of nerve cells called the striatum. Contemporary treatments only minimize the symptoms of this disconnection, as there is no current approach capable of replacing the nigrostriatal pathway. Over the course of our program funded by the Michael J. Fox Foundation, we have developed a suite of micro-biofabrication techniques to enable the creation of the first living, fully-implantable tissue-engineered nigrostriatal pathways (TE-NSPs) that recapitulate key aspects of the structure and function of the native pathway. Through this initial funding, we also demonstrated proof-of-concept that this strategy is able reconstruct the architecture of the native pathway, restore striatal dopamine levels and ease motor deficits in a Parkinson’s model.
Objectives for Supplemental Investigation:
While our initial MJFF program demonstrated proof-of-concept for this tissue engineering strategy to physically replace the nigrostriatal pathway, the observed improvements in striatal dopamine concentration and motor recovery were not consistent and/or sustained across all models. To address this challenge, the current program will systemically optimize the neuronal-axonal density (i.e., tune the “dose” of reestablished axonal inputs to the striatum) and the biomaterial encasement (i.e., more biodegradable and bioresorbable), ultimately towards the goal of consistent, sustained striatal dopamine levels and sustained amelioration of motor deficits. As a step toward clinical translation, we will utilize TE-NSPs biofabricated using human induced pluripotent stem cell (iPSC)-derived dopamine neurons (also developed through our initial MJFF funding).
Importance of This Research for the Development of a New PD Therapy:
We have devised novel microtissue engineering techniques that allow for the biofabrication of the first tissue-engineered nigrostriatal pathway for PD tract reconstruction. The current experimental plan is structured to determine the future translational potential of this strategy by addressing the following question: can human stem cell-derived TE-NSPs physically reconstruct the nigrostriatal pathway to chronically restore dopamine tone in the striatum and improve PD motor symptoms? This strategy has the potential to provide a transformative solution to replace lost neuroanatomy and alleviate the cause of motor symptoms for people with PD.