{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T21:15:06Z","timestamp":1777670106933,"version":"3.51.4"},"reference-count":34,"publisher":"SAGE Publications","issue":"11-12","license":[{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats: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\u2013800\u2009\u03bcL) and rates (0.5\u20135\u2009\u03bcL\/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for \u223c1 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\u2009\u03bcL (2\u2009\u00d7\u2009the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26\u2009h) could have contributed to the generation of larger lesions. The target volume (400\u2009\u03bcL, 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\u2009\u03bcL\/min at a volume \u223c1\/3 of the thalamus (400\u2013600\u2009\u03bcL) appears to be well tolerated in sheep both clinically and histopathologically.<\/jats:p>","DOI":"10.1089\/hum.2019.288","type":"journal-article","created":{"date-parts":[[2020,5,2]],"date-time":"2020-05-02T05:19:36Z","timestamp":1588396776000},"page":"617-625","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model"],"prefix":"10.1177","volume":"31","author":[{"given":"Toloo","family":"Taghian","sequence":"first","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin","family":"Horn","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed Salman","family":"Shazeeb","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey J.","family":"Bierfeldt","sequence":"additional","affiliation":[{"name":"Department of Animal Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan M.","family":"Tuominen","sequence":"additional","affiliation":[{"name":"Department of Animal Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Koehler","sequence":"additional","affiliation":[{"name":"Department of Pathology, Auburn University, Auburn, Alabama, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Fernau","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Bertrand","sequence":"additional","affiliation":[{"name":"Department of Environmental Population Health, Cummings Veterinary School at Tufts University, Grafton, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Frey","sequence":"additional","affiliation":[{"name":"McGill University, Montreal, Canada;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oguz I.","family":"Cataltepe","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"Gounis","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aly H.","family":"Abayazeed","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terence R.","family":"Flotte","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA;"},{"name":"Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Sena-Esteves","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA;"},{"name":"Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather L.","family":"Gray-Edwards","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA;"},{"name":"Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2020,6,12]]},"reference":[{"key":"e_1_3_5_2_2","unstructured":"fda.gov. 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