{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:42:48Z","timestamp":1789188168812,"version":"build-2803163510"},"reference-count":66,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2017,6,1]],"date-time":"2017-06-01T00:00:00Z","timestamp":1496275200000},"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":[[2017,6]]},"abstract":"<jats:p>\n                    GM2 gangliosidoses, including Tay\u2013Sachs disease and Sandhoff disease, are lysosomal storage disorders caused by deficiencies in \u03b2-N-acetylhexosaminidase (Hex). Patients are afflicted primarily with progressive central nervous system (CNS) dysfunction. Studies in mice, cats, and sheep have indicated safety and widespread distribution of Hex in the CNS after intracranial vector infusion of AAVrh8 vectors encoding species-specific Hex \u03b1- or \u03b2-subunits at a 1:1 ratio. Here, a safety study was conducted in cynomolgus macaques (cm), modeling previous animal studies, with bilateral infusion in the thalamus as well as in left lateral ventricle of AAVrh8 vectors encoding cm Hex \u03b1- and \u03b2-subunits. Three doses (3.2\u2009\u00d7\u200910\n                    <jats:sup>12<\/jats:sup>\n                    vg [\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u2009=\u20093]; 3.2\u2009\u00d7\u200910\n                    <jats:sup>11<\/jats:sup>\n                    vg [\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u2009=\u20092]; or 1.1\u2009\u00d7\u200910\n                    <jats:sup>11<\/jats:sup>\n                    vg [\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u2009=\u20092]) were tested, with controls infused with vehicle (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u2009=\u20091) or transgene empty AAVrh8 vector at the highest dose (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u2009=\u20092). Most monkeys receiving AAVrh8-cmHex\u03b1\/\u03b2 developed dyskinesias, ataxia, and loss of dexterity, with higher dose animals eventually becoming apathetic. Time to onset of symptoms was dose dependent, with the highest-dose cohort producing symptoms within a month of infusion. One monkey in the lowest-dose cohort was behaviorally asymptomatic but had magnetic resonance imaging abnormalities in the thalami. Histopathology was similar in all monkeys injected with AAVrh8-cmHex\u03b1\/\u03b2, showing severe white and gray matter necrosis along the injection track, reactive vasculature, and the presence of neurons with granular eosinophilic material. Lesions were minimal to absent in both control cohorts. Despite cellular loss, a dramatic increase in Hex activity was measured in the thalamus, and none of the animals presented with antibody titers against Hex. The high overexpression of Hex protein is likely to blame for this negative outcome, and this study demonstrates the variations in safety profiles of AAVrh8-Hex\u03b1\/\u03b2 intracranial injection among different species, despite encoding for self-proteins.\n                  <\/jats:p>","DOI":"10.1089\/hum.2016.109","type":"journal-article","created":{"date-parts":[[2017,1,28]],"date-time":"2017-01-28T07:55:07Z","timestamp":1485590107000},"page":"510-522","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":85,"title":["Direct Intracranial Injection of AAVrh8 Encoding Monkey \u03b2-N-Acetylhexosaminidase Causes Neurotoxicity in the Primate Brain"],"prefix":"10.1177","volume":"28","author":[{"given":"Diane","family":"Golebiowski","sequence":"first","affiliation":[{"name":"University of Massachusetts Medical School"},{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imramsjah M.J.","family":"van der Bom","sequence":"additional","affiliation":[{"name":"University of Massachusetts Medical School"},{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Churl-Su","family":"Kwon","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Petrosky","sequence":"additional","affiliation":[{"name":"Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison M.","family":"Bradbury","sequence":"additional","affiliation":[{"name":"Auburn University"},{"name":"Auburn University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacy","family":"Maitland","sequence":"additional","affiliation":[{"name":"University of Massachusetts Medical School"},{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Luisa","family":"K\u00fchn","sequence":"additional","affiliation":[{"name":"University of Massachusetts Medical School"},{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Bishop","sequence":"additional","affiliation":[{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Curran","sequence":"additional","affiliation":[{"name":"Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilsa","family":"Silva","sequence":"additional","affiliation":[{"name":"Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwijit","family":"GuhaSarkar","sequence":"additional","affiliation":[{"name":"University of Massachusetts Medical School"},{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan V.","family":"Westmoreland","sequence":"additional","affiliation":[{"name":"Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas R.","family":"Martin","sequence":"additional","affiliation":[{"name":"Auburn University"},{"name":"Auburn University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Gounis","sequence":"additional","affiliation":[{"name":"University of Massachusetts Medical School"},{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wael F.","family":"Asaad","sequence":"additional","affiliation":[{"name":"Brown University"},{"name":"Brown University"},{"name":"Rhode Island Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Sena-Esteves","sequence":"additional","affiliation":[{"name":"University of Massachusetts Medical School"},{"name":"University of Massachusetts Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2017,6,1]]},"reference":[{"key":"e_1_3_3_2_2","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Gravel RA","year":"2001","unstructured":"Gravel RA, , Kaback MM, , Proia RL, et al. The GM2 gangliosidoses. In: Scriver C, , Beaudet AL, , Sly WS, , Valle D, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2011-0078"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-090711-163739"},{"key":"e_1_3_3_5_2","first-page":"120","article-title":"Intravenous injection of purified hexosaminidase A into a patient with Tay\u2013Sachs disease","volume":"9","author":"Johnson WG","year":"1973","unstructured":"Johnson WG, , Desnick RJ, , Long DM, et al. Intravenous injection of purified hexosaminidase A into a patient with Tay\u2013Sachs disease. 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AAV-mediated gene delivery in a feline model of Sandhoff disease corrects lysosomal storage in the central nervous system. 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