Gene-based therapy of Parkinson’s Disease: Translation from animal model to human clinical trial employing convection enhanced delivery

摘要

The existing treatment of Parkinson’s disease (PD) is directed towards substituting dopamine loss with either dopamine replacement therapy or pharmacological therapies aimed at increasing dopamine at the synapse level. Emerging viable alternatives include the use of cell-based and gene-based therapeutics. In this review, we discuss efforts in developing in vitro and in vivo models and their translation to human clinical trials for gene-based therapy of this distressing and prevalent neurodegenerative disorder. Given the mismatch between expectations from preclinical data and results of human pivotal trials, drug delivery has been identified as the key emerging area for translational research due to limitation of limited efficacy. The chief highlights of the current topic include use of improved delivery methods of gene-based therapeutic agents. Convection-enhanced delivery (CED), an advanced infusion technique with demonstrated utility in ex vivo and in vivo animal models has recently been adopted for PD gene-based therapy trials. Several preclinical studies suggest that magnetic resonance imaging (MRI)-guided navigation for accurately targeting and real time monitoring viral vector delivery (rCED) in future clinical trials involving detection of gene expression and restoration of dopaminergic function loss using pro-drug approach will greatly enhance these PD treatments.