{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:02:19Z","timestamp":1779696139828,"version":"3.53.1"},"reference-count":52,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2016,5,19]],"date-time":"2016-05-19T00:00:00Z","timestamp":1463616000000},"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":[[2016,7]]},"abstract":"<jats:p>\n                    G\n                    <jats:sub>M2<\/jats:sub>\n                    gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of G\n                    <jats:sub>M2<\/jats:sub>\n                    ganglioside (G\n                    <jats:sub>M2<\/jats:sub>\n                    ) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (\u03b1\u2013\u03b2), \u201cA\u201d isoenzyme of lysosomal \u03b2-hexosaminidase (HexA). Mutations in the \u03b1-subunit (encoded by\n                    <jats:italic toggle=\"yes\">HEXA<\/jats:italic>\n                    ) lead to Tay-Sachs disease (TSD), whereas mutations in the \u03b2-subunit (encoded by\n                    <jats:italic toggle=\"yes\">HEXB<\/jats:italic>\n                    ) lead to Sandhoff disease (SD). The third form results from a deficiency of the G\n                    <jats:sub>M2<\/jats:sub>\n                    activator protein (G\n                    <jats:sub>M2<\/jats:sub>\n                    AP), a substrate-specific cofactor for HexA. In their infantile, acute forms, these diseases rapidly progress with mental and psychomotor deterioration resulting in death by approximately 4 years of age. After gene transfer that overexpresses one of the deficient subunits, the amount of HexA heterodimer formed would empirically be limited by the availability of the other endogenous Hex subunit. The present study used a new variant of the human HexA \u03b1-subunit, \u03bc, incorporating critical sequences from the \u03b2-subunit that produce a stable homodimer (HexM) and promote functional interactions with the G\n                    <jats:sub>M2<\/jats:sub>\n                    AP\u2013 G\n                    <jats:sub>M2<\/jats:sub>\n                    complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter\u2013intron combination to allow self-complementary (sc) packaging of the\n                    <jats:italic toggle=\"yes\">HEXM<\/jats:italic>\n                    gene. Also, a previously published capsid mutant, AAV9.47, was used to deliver the gene to brain and spinal cord while having restricted biodistribution to the liver. The novel capsid and cassette design combination was characterized\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    in TSD mice for its ability to efficiently transduce cells in the central nervous system when delivered intravenously in both adult and neonatal mice. This study demonstrates that the modified HexM is capable of degrading long-standing G\n                    <jats:sub>M2<\/jats:sub>\n                    storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the\n                    <jats:italic toggle=\"yes\">HEXM<\/jats:italic>\n                    gene or potentially other similar-sized genes to the nervous system.\n                  <\/jats:p>","DOI":"10.1089\/hum.2016.013","type":"journal-article","created":{"date-parts":[[2016,5,20]],"date-time":"2016-05-20T06:21:14Z","timestamp":1463725274000},"page":"509-521","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":43,"title":["Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease"],"prefix":"10.1177","volume":"27","author":[{"given":"Subha","family":"Karumuthil-Melethil","sequence":"first","affiliation":[{"name":"University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahana","family":"Nagabhushan Kalburgi","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Thompson","sequence":"additional","affiliation":[{"name":"Queen's University","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Tropak","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, SickKids, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Kaytor","sequence":"additional","affiliation":[{"name":"New Hope Research Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Keimel","sequence":"additional","affiliation":[{"name":"New Hope Research Foundation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Mark","sequence":"additional","affiliation":[{"name":"University of Manitoba","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don","family":"Mahuran","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, SickKids, Toronto, Ontario, Canada."},{"name":"Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagdeep S.","family":"Walia","sequence":"additional","affiliation":[{"name":"Queen's University","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven 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