Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143-0112, USA.
Mol Ther. 2011 Jun;19(6):1048-57. doi: 10.1038/mt.2011.11. Epub 2011 Feb 22.
Clinical trials involving direct infusion of neurotrophic therapies for Parkinson's disease (PD) have suffered from poor coverage of the putamen. The planned use of a novel interventional-magnetic resonance imaging (iMRI) targeting system for achieving precise, real-time convection-enhanced delivery in a planned clinical trial of adeno-associated virus serotype 2 (AAV2)-glial-derived neurotrophic factor (GDNF) in PD patients was modeled in nonhuman primates (NHP). NHP received bilateral coinfusions of gadoteridol (Gd)/AAV2-GDNF into two sites in each putamen, and three NHP received larger infusion volumes in the thalamus. The average targeting error for cannula tip placement in the putamen was <1 mm, and adjacent putamenal infusions were distributed in a uniform manner. GDNF expression patterns in the putamen were highly correlated with areas of Gd distribution seen on MRI. The distribution volume to infusion volume ratio in the putamen was similar to that in the thalamus, where larger infusions were achieved. Modeling the placement of adjacent 150 and 300 µl thalamic infusions into the three-dimensional space of the human putamen demonstrated coverage of the postcommissural putamen, containment within the striatum and expected anterograde transport to globus pallidus and substantia nigra pars reticulata. The results elucidate the necessary parameters for achieving widespread GDNF expression in the putamenal motor area and afferent substantia nigra of PD patients.
临床研究表明，直接输注神经营养因子治疗帕金森病（PD）的效果不佳，无法完全覆盖壳核。为了在计划开展的帕金森病患者腺相关病毒血清型 2（AAV2）-胶质细胞源性神经营养因子（GDNF）临床试验中实现精确、实时的对流增强递送，计划使用一种新型的介入磁共振成像（iMRI）靶向系统。该系统在非人类灵长类动物（NHP）中进行了建模。NHP 双侧壳核内各两个部位共输注了钆特醇（Gd）/AAV2-GDNF，3 只 NHP 在丘脑内接受了更大的输注体积。在壳核内放置导管尖端的平均靶向误差<1 毫米，且相邻壳核内的输注呈均匀分布。壳核内 GDNF 的表达模式与 MRI 上 Gd 分布的区域高度相关。壳核内的分布体积与输注体积比与丘脑相似，在丘脑内实现了更大的输注体积。将相邻的 150 和 300µl 丘脑输注物放置在人类壳核的三维空间中，模拟了对壳核后连合区的覆盖，包含在纹状体内部，并预期向苍白球和黑质网状部进行顺行转运。这些结果阐明了在 PD 患者壳核运动区和黑质传入区实现广泛 GDNF 表达所需的参数。
