Innovative systemic gene therapy for treating Parkinson's disease

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PROJECT SUMMARY Parkinson's disease (PD) is an increasingly prevalent neurological disorder that currently affects about one million people in the United States and 10 million worldwide. Despite recent innovations, most advanced pharmacological and surgical therapeutic regimens remain moderately palliative and symptomatic at best. Gene therapy has emerged as an alternative promising means to halt the disease progression or potentially cure the disease. However, clinical trials of PD gene therapy up to this moment have failed to establish a meaningful therapeutic benefit due to an inability to achieve widespread and efficient gene transfer to the disease areas within the brain. The significance of this problem is highlighted by an ongoing human trial, wherein improving the penetration and efficiency of transfection is a primary goal. Further, lacking a reliable method to deploy gene therapy from the bloodstream to the brain tissue, all clinical studies to date have employed highly invasive administration modalities involving direct injection of the therapy into the brain. This reality has precluded the inclusion in clinical trials of early stage PD patients who are more likely to respond to the therapy. Thus, new methods to overcome long-standing barriers to systemic gene delivery throughout the PD-associated brain regions, including the tightly sealed blood-brain barrier (BBB) and the dense network of brain extracellular matrix (ECM), are sorely needed. To this end, we propose innovative delivery approaches exploiting: (i) clinically operable MR image-guided focused ultrasound (FUS) to transiently open the BBB for the penetration of gene therapy into the brain tissues and cells in a targeted manner, (ii) DNA-loaded nanoparticles possessing a unique capability to efficiently spread through the brain ECM to reach and transfect cells in the disease areas within the brain (i.e. DNA-loaded brain-penetrating nanoparticle or DNA-BPN), and (iii) FUS-mediated pre-conditioning that further enhances the dispersion of DNA-BPN within the brain by temporarily reducing ECM resistance. We recently showed in our pilot study that FUS-mediated, targeted BBB penetration of, and subsequent widespread gene transfer by, our first-generation DNA-BPN resulted in therapeutically relevant gene therapy of a conventional neurotoxin-based preclinical model of PD. As a next step towards clinical translation, we here propose to further refine and evaluate our combined delivery strategy in highly sophisticated and clinically-relevant preclinical models of familial and sporadic PD that closely mimic pathophysiological features and disease phenotypes observed in human PD. If successful, the proposed approach could be rapidly translated to the clinic using a gene-encoding a neurotrophic factor (that is currently under clinical investigation and will be studied here) while additional preclinical studies could be followed to test the effectiveness of novel genetic targets in these advanced PD models. In addition, the approach could also be applied to other neurological disorders characterized by highly disseminated disease areas within the brain.