Viral Vector-Mediated Trophic Support for Transplanted hESC-Derived Dopaminergic Cells in a SynFib Rat Model of Parkinson’s Disease

Parkinson’s Disease (PD) is a progressive neurodegenerative disease that has no cure and affects over twelve million people worldwide with its progressive dysfunction. Its motor and non-motor dysfunctions can be associated with the loss of dopamine producing neurons in the CNS, making studies that focus on replenishing said loss an important step in increasing the afllicted’s quality. Cell therapies for the transplantation of dopaminergic progenitors into the Nigrostriatal Pathway have shown to be a viable alternative in vivo for reducing motor dysfunction and increasing neuronal survivability. The work performed by Anders Björklund’s group showed not only the efficacy of dopaminergic transplantation in reducing dysfunction, but also the capability of a α-Syn+PFF PD model in displaying the progressive nature of the disease. In order to increase the possible survival rate of the transplanted cells, and to hopefully modify the progression of the pathology model, this project introduced AAVs containing expression cassettes for the MANF and CDNF Trophic Factors to the Dopaminergic Progenitors grafted onto Adult Hsd:RH-Fox1rnu female rats that had the α-Syn+PFF model applied to them. The model was allowed to develop, and behavioral tests were applied at 3 separate time points in order to quantify motor dysfunction. The animal tissue was collected, and immunohistochemical analysis was performed to quantify the survival rates of Dopaminergic Cells in the Substantia Nigra. Even though no statistically significant difference was seen in the reduction of the motor dysfunction amongst the groups treated with the dopaminergic progenitors and the Sham control group, there was a statistically significant increase in the survival rate of dopamine neurons in the Substantia Nigra in the rats treated with AAV-C-MANF. This continuation of previous works may serve as evidence that providing trophic support in combination with dopaminergic progenitor grafts enhances graft survival and dopaminergic neuron preservation, indicating that such combined strategies may represent a promising avenue for future therapies.