Bankiewicz Krystof S, Daadi Marcel, Pivirotto Philip, Bringas John, Sanftner Laura, Cunningham Janet, Forsayeth John R, Eberling Jamie L
Department of Neurological Surgery, University of California San Francisco, Mission Center Building 0555, 1855 Folsom Street, Room 230, 94103, USA.
Exp Neurol. 2006 Feb;197(2):363-72. doi: 10.1016/j.expneurol.2005.10.022. Epub 2005 Dec 9.
Striatal neurons convert L-dopa to dopamine (DA) following gene transfer of aromatic L-amino acid decarboxylase (AADC) via adeno-associated virus (AAV) in parkinsonian monkeys. We investigated whether AAV-AADC could reduce or eliminate L-dopa-induced dyskinesias (LIDs) and side effects in MPTP-treated monkeys. Five monkeys were made parkinsonian by bilateral MPTP lesions. The optimal therapeutic dose of L-dopa was determined using an acute dose response regimen. After 3 weeks of chronic L-dopa treatment, AAV-AADC or control vector was bilaterally injected into the striatum. Animals were assessed for 6 months with the same L-dopa dosing as presurgery as well as chronic oral L-dopa treatment. Presurgery LID was observed at doses greater than 5 mg/kg. The AAV-AADC-treated animals displayed an average 7.3-fold decrease in the therapeutic dose of L-dopa throughout the 6-month follow-up period. Only AAV-AADC-treated monkeys were susceptible to dyskinesias even at sub-clinical doses. Immunohistochemical analysis revealed well-delineated foci of AADC within the striatum. These results suggest that high levels of focal DA were generated in response to L-dopa administration and may be responsible for the exacerbation of dyskinesias. This may be similar to focal dopaminergic activity in PD patients that developed off-drug or "runaway" dyskinesias following fetal mesencephalic grafts.
在帕金森病猴中，通过腺相关病毒（AAV）进行芳香族L-氨基酸脱羧酶（AADC）基因转移后，纹状体神经元可将左旋多巴转化为多巴胺（DA）。我们研究了AAV-AADC是否能减少或消除MPTP处理的猴子中左旋多巴诱导的运动障碍（LIDs）及副作用。通过双侧MPTP损伤使5只猴子患帕金森病。使用急性剂量反应方案确定左旋多巴的最佳治疗剂量。在慢性左旋多巴治疗3周后，将AAV-AADC或对照载体双侧注射到纹状体中。对动物进行6个月的评估，给药剂量与术前相同，同时进行慢性口服左旋多巴治疗。在剂量大于5mg/kg时观察到术前LID。在整个6个月的随访期内，接受AAV-AADC治疗的动物左旋多巴治疗剂量平均降低了7.3倍。即使在亚临床剂量下，只有接受AAV-AADC治疗的猴子易患运动障碍。免疫组织化学分析显示纹状体内有界限清晰的AADC病灶。这些结果表明，给予左旋多巴后产生了高水平的局灶性DA，这可能是运动障碍加重的原因。这可能与帕金森病患者在接受胎儿中脑移植后出现的停药或“失控”运动障碍时的局灶性多巴胺能活动类似。
