Dopaminergic Cell Replacement for Parkinson’s Disease: Addressing the Intracranial Delivery Hurdle

Parkinson’s disease (PD) is an increasingly prevalent neurological disorder, affecting more than 8.5 million individuals worldwide. α-Synucleinopathy in PD is considered to cause dopaminergic neuronal loss in the substantia nigra, resulting in characteristic motor dysfunction that is the target for current medical and surgical therapies. Standard treatment for PD has remained unchanged for several decades and does not alter disease progression. Furthermore, symptomatic therapies for PD are limited by issues surrounding long-term efficacy and side effects. Cell replacement therapy (CRT) presents an alternative approach that has the potential to restore striatal dopaminergic input and ameliorate debilitating motor symptoms in PD. Despite promising pre-clinical data, CRT has demonstrated mixed success clinically. Recent advances in graft biology have renewed interest in the field, resulting in several worldwide ongoing clinical trials. However, factors surrounding the effective neurosurgical delivery of cell grafts have remained under-studied, despite their significant potential to influence therapeutic outcomes. Here, we focus on the key neurosurgical factors to consider for the clinical translation of CRT. We review the instruments that have been used for cell graft delivery, highlighting current features and limitations, while discussing how future devices could address these challenges. Finally, we review other novel developments that may enhance graft accessibility, delivery, and efficacy. Challenges surrounding neurosurgical delivery may critically contribute to the success of CRT, so it is crucial that we address these issues to ensure that CRT does not falter at the final hurdle.