Trophic gene transfer in MPTP animals

University Of Rochester, Rochester NY

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Abstract

The long-term goal of this project is to apply neurotrophic factor gene therapy to patients with Parkinson's disease (PD). Extensive basic research in rodent and monkey models of PD indicates that the neurotrophic factor, glial cell ine-derived neurotrophic factor (GDNF) can slow the degeneration of dopamine (DA) neurons in the substantial nigra (SN); neurons that die in PD. Moreover, local delivery of these factors into the brain (using vector mediated gene transport) has shown protection of neurochemical, cellular and behavioral indices of DA function in 6-OHDA or MPTP lesioned animal models. Gene delivery was also shown to increase growth factor synthesis in a chronic manner within the vicinity of DA neurons; an advantage for treating slowly progressive CNS disorders such as PD. Thus, basic research strongly supports GDNF gene therapy as a novel treatment for PD. However, several issues require addressing prior to designing a clinical trial. First, identifying optimal vector system for gene delivery; this project will compare adeno-associated (AAV) and lentiviral vector systems which appear to be two most promising vector systems for transducing brain tissue. Secondly, it is not known whether GDNF gene delivery will ameliorate the parkinsonian condition in primates that have a stable, chronic lesion of the DA system. This project will use a primate model that closely reflects the mild clinical state of the disease. Thirdly, regulating gene expression will play an important role following therapeutic intervention to offset side-effects that may occur due to growth factor overexpression. Therefore, this revised project will evaluate adeno-associated viral (AAV) vectors in which the transgene can be regulated by peripheral doxycycline (Dox) administration. In summary, Dox regulated AAV and lentivral vectors will be produced and characterized in the rodent brain prior to initiating primate studies. High titer, helper-free clinical grade vectors prepared in a GLP facility will be used for primate studies. Vectors will be injected into the primate striatum using convection-enhanced delivery methods. Transgene expression and biological effects will be evaluated by a variety of behavioral, neurochemical, morphologic and molecular assays including, but not limited to in vivo FMT PET imaging, MRI, clinical rating and clinical responses to L-DOPA administration, HPLC, ELISA, in situ hybridization, immunocytochemistry, stereology and toxicology. These studies will involve collaborations within PDGTSG and will provide data leading to a clinical trial for Parkinson's disease. Results from these studies may also be applied for treating other neurodegenerative diseases and injuries related to the CNS.