Gene Delivery to the CNS through the Deep Cerebellar Nucleus

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DESCRIPTION (provided by applicant): In pursuit of improving gene delivery to all areas of the CNS in a safe and efficient manner, the objective of this proposal is to develop, optimize, and test this alternate delivery route to overcome the limitations of the blood brain barrier, which is a specific focus of this Request for Applications. Our strategy is centered on a specialized region of the brain termed the deep cerebellar nuclei (DCN). We will employ Adeno- Associated Viral Vector (AAV), a vector that has shown to be non-pathogenic with safety profiles being established in numerous human clinical trials as well as initial signs of clinical success in diseases such as Parkinson's disease and a viral vector that we have considerable experience with 1, 2 . We have recently examined this novel global gene delivery approach in a mouse model for Amyotrophic Lateral Sclerosis (ALS) with the approach appearing to be robust and therefore feasible. Several reports have shown the potential actions of neurotrophic factors to delay disease onset and progression 4-6 . However, challenges still remain to effectively translate these approaches to the clinic. We hypothesize that this one-time single injection delivery strategy to the DCN will result in global CNS transduction, allowing for widespread trophic support to the brainstem, spinal cord and motor cortex. We further hypothesize that this approach will greatly increase motor coordination, extend survival, and rescue neuropathological symptoms when the delivery approach is tested in ALS transgenic mice. The main goal of this proposal is to define a more effective therapeutic route for global gene delivery utilizing an AAV vector. This approach may be amenable for treating multiple neurological diseases and conditions, primarily associated either with the spinal cord such as ALS and spinal cord injury, or with the brain such as Alzheimer's and Parkinson's Disease. Our specific aims are shown below. 1.) To determine whether a single injection of AAV to the DCN targets the CNS and all regions of the spinal cord. 2.) To determine the efficacy of DCN gene delivery of AAV-IGF-1 in an animal model of ALS. Current gene therapy remains to be a challenge due to effective methods to target the CNS including the difficulty to access the spinal cord. Systemic delivery of gene therapy vectors to the CNS has been challenging due largely by their inability to cross the blood-brain barrier (BBB). Our strategy is centered on targeting a specialized region of the brain termed the deep cerebellar nuclei (DCN) with adeno-associated vectors (AAV) to deliver transgenes. We have decided to target the DCN because of its extensive connections with all regions of the spinal cord and brainstem, and would thus serve as an ideal gene delivery route.