Treatments for Parkinson's disease (PD) have historically focused on symptomatic relief, rather than therapies that alter the natural progression of the disease. Neurotrophic factors promote survival, differentiation, and maintenance of the nigrostriatal system and may have the potential to slow and reverse neurodegenerative processes. To date, exogenous administration of neurotrophic factors by gene therapy has been the most promising approach to ameliorate motor symptoms and stall disease progression. Preliminary studies have shown that viral vector-mediated overexpression in the nigrostriatal system of the neurotrophic factor pleiotrophin (PTN) provides neuroprotection and functional restoration in a 6-hydroxydopamine (6-OHDA) rodent model of PD. PTN is a potent cell survival and neurite outgrowth-promoting factor both in the developing and lesioned nigrostriatal system. PTN protein and receptors are expressed by mesencephalic dopamine (DA) neurons and are upregulated in response to striatal denervation and other nervous system injuries. PTN and its receptors are highly upregulated in the surviving nigral DA neurons of PD patients. Although PTN can protect SN DA neurons when administered prior to insult, morphological restoration and functional recovery after significant DA neuron loss are necessary for clinical application.
Aim 1 will examine the therapeutic potential of PTN overexpression, generated by nigrostriatal injections of adeno-associated viral vectors encoding for PTN, following significant DA neuron and terminal loss by 6-OHDA.
Aim 2 will test the therapeutic potential of PTN overexpression following significant DA neuron and terminal loss by ?-synuclein (?-syn) overexpression. ? -syn rodent models exhibit ?-syn containing neuron bodies and dystrophic neurites that neurotoxin models fail to recapitulate. Neurotrophic factors that elicit positive effects in animal models mimicking both pathological hallmarks of PD, nigral cell death and Lewy body formation, have greater potential to be clinically beneficial to PD patients. The long-term goal of this proposal is to determine if PTN gene transfer can be used as a therapeutic strategy to treat PD after significant nigrostriatal damage has already occurred. The objective of this proposal is to determine the potential of PTN gene therapy to halt ongoing nigrostriatal degeneration and provide both morphological and functional restoration in rat models of PD. The central hypothesis is that overexpression of PTN in the damaged rat nigrostriatal system can facilitate long- term morphological and functional recovery in both the 6-OHDA and ?-syn parkinsonian models. These results may ultimately determine if PTN gene transfer can be used as a therapeutic option for PD and other nervous system disorders.
Parkinson's disease is a progressive neurodegenerative disorder without a cure, and disease prevalence is predicted to increase with the growing aging population. Parkinson's disease is commonly diagnosed with the onset of motor symptoms, and amelioration of symptoms is the primary focus of current therapies. Gene therapy strategies that apply exogenous application of neurotrophic factors, proteins involved in neuron growth and survival, have the potential to both restore normal motor function and stop disease progression. In this proposal we aim to test the therapeutic potential of the neurotrophic factor pleiotrophin, delivered by viral vectors, to morphologically protect degenerating pathways and restore function in two rodent models of parkinsonism.
|Gombash, S E; Manfredsson, F P; Mandel, R J et al. (2014) Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways. Gene Ther 21:682-93|
|Gombash, Sara E; Manfredsson, Fredric P; Kemp, Christopher J et al. (2013) Morphological and behavioral impact of AAV2/5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system. PLoS One 8:e81426|