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dc.contributor.authorTaghian, Toloo
dc.contributor.authorHorn, Erin
dc.contributor.authorShazeeb, Mohammed S.
dc.contributor.authorBierfeldt, Lindsey J.
dc.contributor.authorTuominen, Susan M.
dc.contributor.authorKoehler, Jennifer
dc.contributor.authorFernau, Deborah
dc.contributor.authorBertrand, Stephanie
dc.contributor.authorFrey, Stephen
dc.contributor.authorCataltepe, Oguz
dc.contributor.authorGounis, Matthew J.
dc.contributor.authorAbayazeed, Aly
dc.contributor.authorFlotte, Terence R.
dc.contributor.authorSena-Esteves, Miguel
dc.contributor.authorGray-Edwards, Heather L
dc.date2022-08-11T08:10:49.000
dc.date.accessioned2022-08-23T17:21:02Z
dc.date.available2022-08-23T17:21:02Z
dc.date.issued2020-06-01
dc.date.submitted2020-06-17
dc.identifier.citation<p>Taghian T, Horn E, Shazeeb MS, Bierfeldt LJ, Tuominen SM, Koehler J, Fernau D, Bertrand S, Frey S, Cataltepe OI, Gounis MJ, Abayazeed AH, Flotte TR, Sena-Esteves M, Gray-Edwards HL. Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model. Hum Gene Ther. 2020 Jun;31(11-12):617-625. doi: 10.1089/hum.2019.288. Epub 2020 May 29. PMID: 32363942. <a href="https://doi.org/10.1089/hum.2019.288">Link to article on publisher's site</a></p>
dc.identifier.issn1043-0342 (Linking)
dc.identifier.doi10.1089/hum.2019.288
dc.identifier.pmid32363942
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48433
dc.description.abstractThalamic 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 muL) and rates (0.5-5 muL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for approximately 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 muL (2 x 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 muL, 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 muL/min at a volume approximately 1/3 of the thalamus (400-600 muL) appears to be well tolerated in sheep both clinically and histopathologically.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32363942&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1089/hum.2019.288
dc.subjectGM2 gangliosidoses
dc.subjectSandhoff
dc.subjectTay-Sachs
dc.subjectintraparenchymal injection
dc.subjectthalamic injection
dc.subjectthalamic pain syndrome
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.subjectRadiology
dc.subjectTherapeutics
dc.titleVolume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model
dc.typeJournal Article
dc.source.journaltitleHuman gene therapy
dc.source.volume31
dc.source.issue11-12
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/radiology_pubs/540
dc.identifier.contextkey18142178
html.description.abstract<p>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 muL) and rates (0.5-5 muL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for approximately 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 muL (2 x 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 muL, 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 muL/min at a volume approximately 1/3 of the thalamus (400-600 muL) appears to be well tolerated in sheep both clinically and histopathologically.</p>
dc.identifier.submissionpathradiology_pubs/540
dc.contributor.departmentDepartment of Neurology
dc.contributor.departmentDepartment of Pediatrics
dc.contributor.departmentDepartment of Neurological Surgery
dc.contributor.departmentDepartment of Animal Medicine
dc.contributor.departmentDepartment of Radiology
dc.contributor.departmentHorae Gene Therapy Center
dc.source.pages617-625


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