The Effects Of Gene Therapy With Conserved Dopamine Neurotrophic Factor Deliveried By RAAV-8 On Rat Parkinson's Models

The main clinical symptoms of Parkinson's disease are tremor,paralysis,muscle rigidity,bradykinesia.It is one of the most common central nervous system degenerative diseases.Since it was found in 1817,researches on Parkinson's disease have been in constant,however,the pathogenesis is still unclear so far.The most important pathological features of Parkinson's disease is the damage of dopaminergic neurons on the substantia nigra striatum pathway,leading to the dopamine levels decreased in the striatum.Then the imbalance of excitatory neurotransmitter and inhibitory neurotransmitter appears,which lead to disorders of individual sports.There are many different ways of drug delivery:oral drugs,brain surgery,cell transplantation and gene therapy,and different therapeutic targets according to different symptoms and pathological features:dopamine synthesis alternative,neurotrophic factor protection,histone acetylation,a-synapse nucleoprotein,microglial neurons,genetic genes,etc.The most important thing in the current research,is not only to explore the exact etiology and find more effective targets,more importantly,but also to achieve the best therapeutic effect by selecting the appropriate therapeutic targets,in order to suit a way of drug delivery,within the scope of the known.Conservative dopamine neurotrophic factor(CDNF)was discovered in 2007.It is a kind of secretory proteins which is expressed in brain cortex,substantia nigra,heart,liver,cerebellum,skeletal muscle and other tissues.Studies have shown that CDNF could significantly protect and repair dopaminergic neurons,and it is more effective when compared with GDNF,MANF and other types of neurotrophic factors.Therefore,we selected the neurotrophic factor CDNF as the main therapeutic targets,using gene therapy drug delivery methods,with AAV-8 virus as gene therapy vectors,the 6-OHDA injury treatment of Parkinson's disease rat model,discusses the effect of CDNF on protecting and repairing the nervous system.In this study,we got 3 rAAV:AAV-CDNF,AAV-AADC,AAV-RFP.Then,we proved that CDNF has protective effect on the 6-OHDA damaged PC 12 cell.In vivo,CDNF prevented the 6-OHDA-induced degeneration of dopaminergic neurons in rats.Injection of AAV-CDNF soon after 6-OHDA delivery into the striatum significantly reduced amphetamine-induced ipsilateral turning behavior.In this paper,the results show that AAV-8 as a deliverer of gene therapy,could help exogenous fragments deliver into rats and expressed in a large number.CDNF showed very good protection effect of dopaminergic neurons in vivo and in vitro and it would become a very important target for the follow-up study.