Parkinson Hastalığı İçin Terapötiklerin Geliştirilmesi İçin Alfa-Synükleinopatinin İnsan Dışı Bir Primat Modeline Doğru: Macaque'de Alfa Synüklein ve Dopaminerjik Dejenerasyonun Sürdürülebilir İfadesini Sürdürmek için AAV1/2 Teslim Parametrelerinin Optimizasyonu.

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Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 μl per site, 1.7 x 1012 gp/ml), this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform.

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