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Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson’s disease
Molecular Therapy ( IF 12.4 ) Pub Date : 2022-08-10 , DOI: 10.1016/j.ymthe.2022.08.003
Matthew T Rocco 1 , Asad S Akhter 1 , Debra J Ehrlich 2 , Gretchen C Scott 3 , Codrin Lungu 4 , Vikas Munjal 1 , Anthony Aquino 5 , Russell R Lonser 1 , Massimo S Fiandaca 6 , Mark Hallett 7 , John D Heiss 3 , Krystof S Bankiewicz 1
Affiliation  

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson’s disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.



中文翻译:

MRI 引导下帕金森病患者壳核 AAV2-GDNF 和钆特醇给药的长期安全性

在晚期帕金森病 (PD) 参与者的 I 期临床试验中研究了直接壳核输注含有人神经胶质细胞系衍生神经营养因子 (GDNF) 转基因的腺相关病毒载体(血清型 2)(AAV2)。在实时术中磁共振成像 (iMRI) 期间,使用替代成像示踪剂(钆特醇)增强 AAV2-GDNF 的对流递送来跟踪输液分布。对 13 名接受双侧壳核联合输注(共输注 52 次)AAV2-GDNF 和钆特醇(输注量为 450 mL)的 PD 患者进行术前、术中和连续术后(输注后长达 5 年)的 MRI 分析每个壳核)。实时 iMRI 确认输液套管放置,壳核内体积灌注的解剖量化,直接可视化脱靶泄漏或插管回流(允许相应的输注速率/插管调整)。一系列治疗后 MRI 评估(n = 13)表明,在长期随访中,AAV2-GDNF 和加多利多联合输注的相应区域或周围区域没有脑实质毒性的证据。关键术中安全性和有效性参数的直接确认强调了联合输注加多利多和推定治疗剂(即 AAV2-GDNF)的实时成像的安全性和组织靶向价值。这种递送成像平台提高了安全性,允许递送个性化,改善治疗分配,并促进疗效和剂量效果的评估。一系列治疗后 MRI 评估(n = 13)表明,在长期随访中,AAV2-GDNF 和加多利多联合输注的相应区域或周围区域没有脑实质毒性的证据。关键术中安全性和有效性参数的直接确认强调了联合输注加多利多和推定治疗剂(即 AAV2-GDNF)的实时成像的安全性和组织靶向价值。这种递送成像平台提高了安全性,允许递送个性化,改善治疗分配,并促进疗效和剂量效果的评估。一系列治疗后 MRI 评估(n = 13)表明,在长期随访中,AAV2-GDNF 和加多利多联合输注的相应区域或周围区域没有脑实质毒性的证据。关键术中安全性和有效性参数的直接确认强调了联合输注加多利多和推定治疗剂(即 AAV2-GDNF)的实时成像的安全性和组织靶向价值。这种递送成像平台提高了安全性,允许递送个性化,改善治疗分配,并促进疗效和剂量效果的评估。关键术中安全性和有效性参数的直接确认强调了联合输注加多利多和推定治疗剂(即 AAV2-GDNF)的实时成像的安全性和组织靶向价值。这种递送成像平台提高了安全性,允许递送个性化,改善治疗分配,并促进疗效和剂量效果的评估。关键术中安全性和有效性参数的直接确认强调了联合输注加多利多和推定治疗剂(即 AAV2-GDNF)的实时成像的安全性和组织靶向价值。这种递送成像平台提高了安全性,允许递送个性化,改善治疗分配,并促进疗效和剂量效果的评估。

更新日期:2022-08-10
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