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Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model.
Human Gene Therapy ( IF 4.2 ) Pub Date : 2020-06-12 , DOI: 10.1089/hum.2019.288
Toloo Taghian 1 , Erin Horn 1 , Mohammed Salman Shazeeb 2 , Lindsey J Bierfeldt 3 , Susan M Tuominen 3 , Jennifer Koehler 4 , Deborah Fernau 1 , Stephanie Bertrand 5 , Stephen Frey 6 , Oguz I Cataltepe 7 , Matthew J Gounis 2 , Aly H Abayazeed 2 , Terence R Flotte 1, 8 , Miguel Sena-Esteves 1, 9 , Heather L Gray-Edwards 1, 2
Affiliation  

Thalamic infusion of adeno-associated viral (AAV) vectors has been shown to have therapeutic effects in neuronopathic lysosomal storage diseases. Preclinical studies in sheep model of Tay-Sachs disease demonstrated that bilateral thalamic injections of AAV gene therapy are required for maximal benefit. Translation of thalamic injection to patients carries risks in that (1) it has never been done in humans, and (2) dosing scale-up based on brain weight from animals to humans requires injection of larger volumes. To increase the safety margin of this infusion, a flexible cannula was selected to enable simultaneous bilateral thalamic infusion in infants while monitoring by imaging and/or to enable awake infusions for injection of large volumes at low infusion rates. In this study, we tested various infusion volumes (200–800 μL) and rates (0.5–5 μL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for ∼1 month postinjection with magnetic resonance imaging (MRI) performed at 14 and 28 days. T1-weighted MRI was used to quantify thalamic damage followed by histopathological assessment of the brain. Trends in data show that infusion volumes of 800 μL (2 × the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26 h) could have contributed to the generation of larger lesions. The target volume (400 μL, projected to be sufficient to cover most of the sheep thalamus) created the smallest lesion size. Cannula placement alone did result in damage, but this is likely associated with an inherent limitation of its use in a small brain due to the length of the distal rigid portion and lack of stable fixation. An injection rate of 5 μL/min at a volume ∼1/3 of the thalamus (400–600 μL) appears to be well tolerated in sheep both clinically and histopathologically.

中文翻译:

大型动物模型中实质内中枢神经系统输注的体积和输注速率动力学。

腺相关病毒 (AAV) 载体的丘脑输注已被证明对神经性溶酶体贮积病具有治疗作用。Tay-Sachs 病绵羊模型的临床前研究表明,需要双侧丘脑注射 AAV 基因治疗才能获得最大益处。将丘脑注射液转化为患者存在风险,因为 (1) 从未在人类中进行过,以及 (2) 基于脑重量从动物到人类的剂量放大需要更大体积的注射。为了增加这种输注的安全范围,选择了一种灵活的套管,以便在通过成像监测的同时对婴儿进行双侧丘脑输注,和/或能够以低输注速率进行大容量注射的清醒输注。在本研究中,我们测试了各种输注体积 (200–800 μL) 和速率 (0. 5–5 μL/min) 以确定进样参数的最大耐受组合。在注射后 14 天和 28 天用磁共振成像 (MRI) 对动物进行随访约 1 个月。T1 加权 MRI 用于量化丘脑损伤,然后对大脑进行组织病理学评估。数据趋势表明,800 μL 的输注体积(2 倍于基于丘脑大小的绵羊所需的体积)导致比较小体积更大的病变,其中较长的输注时间(13 至 26 小时)可能有助于产生较大的病变。目标体积(400 μL,预计足以覆盖大部分绵羊丘脑)产生最小的病变尺寸。单独放置套管确实会导致损坏,但这可能与由于远端刚性部分的长度和缺乏稳定的固定而在小脑中使用的固有限制有关。从临床和组织病理学上看,以 5 μL/min 的速度注射 1/3 体积的丘脑(400-600 μL)似乎对绵羊具有良好的耐受性。
更新日期:2020-06-12
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