Kinetics and MR-Based Monitoring of AAV9 Vector Delivery into Cerebrospinal Fluid of Nonhuman Primates
Autor: | Lluis Samaranch, John Forsayeth, Waldy San Sebastian, Krystof S. Bankiewicz, Ernesto A. Salegio, Philip C. Allen, Piotr Hadaczek, Haifeng Chen, Michael V. Campagna, Jerusha Naidoo, Granger G.C. Hwa, Kousaku Ohno, John Bringas, Vivek Sudhakar, Diane E. Stockinger, Christopher Snieckus |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
lcsh:QH426-470 MRI contrast agent intracerebroventricular intrathecal infusion Cisterna magna Article cerebrospinal fluid 03 medical and health sciences 0302 clinical medicine Lumbar Cerebrospinal fluid medicine Genetics Distribution (pharmacology) magnetic resonance imaging lcsh:QH573-671 Molecular Biology lumbar Gadoteridol medicine.diagnostic_test business.industry lcsh:Cytology Neurosciences Magnetic resonance imaging cisterna magna Gene Therapy Spinal cord gene therapy AAV vector lcsh:Genetics 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Molecular Medicine Biomedical Imaging non-human primates Nuclear medicine business pharmacokinetics medicine.drug |
Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 13, Iss, Pp 47-54 (2019) Molecular Therapy. Methods & Clinical Development |
ISSN: | 2329-0501 |
Popis: | Here we evaluated the utility of MRI to monitor intrathecal infusions in nonhuman primates. Adeno-associated virus (AAV) spiked with gadoteridol, a gadolinium-based MRI contrast agent, enabled real-time visualization of infusions delivered either via cerebromedullary cistern, lumbar, cerebromedullary and lumbar, or intracerebroventricular infusion. The kinetics of vector clearance from the cerebrospinal fluid (CSF) were analyzed. Our results highlight the value of MRI in optimizing the delivery of infusate into CSF. In particular, MRI revealed differential patterns of infusate distribution depending on the route of delivery. Gadoteridol coverage analysis showed that cerebellomedullary cistern delivery was a reliable and effective route of injection, achieving broad infusate distribution in the brain and spinal cord, and was even greater when combined with lumbar injection. In contrast, intracerebroventricular injection resulted in strong cortical coverage but little spinal distribution. Lumbar injection alone led to the distribution of MRI contrast agent mainly in the spinal cord with little cortical coverage, but this delivery route was unreliable. Similarly, vector clearance analysis showed differences between different routes of delivery. Overall, our data support the value of monitoring CSF injections to dissect different patterns of gadoteridol distribution based on the route of intrathecal administration. Keywords: gene therapy, AAV vector, non-human primates, intrathecal infusion, cisterna magna, lumbar, intracerebroventricular, pharmacokinetics, magnetic resonance imaging, cerebrospinal fluid |
Databáze: | OpenAIRE |
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