Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease
GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subu...
Gespeichert in:
Veröffentlicht in: | Human gene therapy 2016-07, Vol.27 (7), p.509-521 |
---|---|
Hauptverfasser: | , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 521 |
---|---|
container_issue | 7 |
container_start_page | 509 |
container_title | Human gene therapy |
container_volume | 27 |
creator | Karumuthil-Melethil, Subha Nagabhushan Kalburgi, Sahana Thompson, Patrick Tropak, Michael Kaytor, Michael D Keimel, John G Mark, Brian L Mahuran, Don Walia, Jagdeep S Gray, Steven J |
description | GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), 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 α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM 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 in vivo 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 GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system. |
doi_str_mv | 10.1089/hum.2016.013 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5349231</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1805763049</sourcerecordid><originalsourceid>FETCH-LOGICAL-c511t-ba3f9d0f36c97b1d0d72f856c67f9ec95bad5237c41f833748581e07773257ca3</originalsourceid><addsrcrecordid>eNqNkktv1DAUhS0EoqWwY40ssemCDH7GyQZpNG0pUgWLDrO1HOd6xlViD3ZS0X_Az65HLRWwYuUr-dO5j3MQekvJgpKm_bibxwUjtF4Qyp-hYyqlqpRg7HmpieAV4YIdoVc535BCyFq9REdM0VZJ0RyjX1_jLQx4A3aKCZ9B9tuATejxJfyM2Yw--N5kwBuTvAkTPg-mG3zY4msYXLWK436AEcJk0h1e9hBitcw5Wm8m6PHGpzljV4SnHeB1AjMdWBwdXpu76trYXcZnPkPp8Bq9cGbI8ObxPUHfL87Xq8vq6tvnL6vlVWUlpVPVGe7anjhe21Z1tCe9Yq6Rta2Va8G2sjO9ZFxZQV3DuRKNbCgQpRRnUlnDT9CnB9393I3Q2zJPMoPeJz-WHXQ0Xv_9E_xOb-Otlly0jNMicPookOKPGfKkR58tDIMJEOesadNQJVrB-H-gRKqaE9EW9P0_6E2cUyiX0Ky4RhWV6kB9eKBsijkncE9zU6IPadAlDfqQBl28Lvi7P3d9gn_bz-8BgIGxiA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2135171579</pqid></control><display><type>article</type><title>Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Karumuthil-Melethil, Subha ; Nagabhushan Kalburgi, Sahana ; Thompson, Patrick ; Tropak, Michael ; Kaytor, Michael D ; Keimel, John G ; Mark, Brian L ; Mahuran, Don ; Walia, Jagdeep S ; Gray, Steven J</creator><creatorcontrib>Karumuthil-Melethil, Subha ; Nagabhushan Kalburgi, Sahana ; Thompson, Patrick ; Tropak, Michael ; Kaytor, Michael D ; Keimel, John G ; Mark, Brian L ; Mahuran, Don ; Walia, Jagdeep S ; Gray, Steven J</creatorcontrib><description>GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), 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 α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM 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 in vivo 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 GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2016.013</identifier><identifier>PMID: 27197548</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Adeno-associated virus ; Animals ; Animals, Newborn ; Brain ; Central nervous system ; Dependovirus - genetics ; Design ; Disease ; Disease Models, Animal ; Female ; G(M2) Ganglioside - metabolism ; Ganglioside GM2 ; Gangliosidosis ; Gene transfer ; Genetic Therapy ; Genetic Vectors - administration & dosage ; Genomes ; Hexosaminidases - genetics ; Liver ; Liver - metabolism ; Medical treatment ; Mice ; Mice, Inbred C57BL ; Mutation ; Mutation - genetics ; Neonates ; Nervous system ; Neurodegenerative diseases ; Packaging ; Proteins ; Spinal cord ; Substrates ; Tay-Sachs disease ; Tay-Sachs Disease - genetics ; Tay-Sachs Disease - therapy ; Viruses</subject><ispartof>Human gene therapy, 2016-07, Vol.27 (7), p.509-521</ispartof><rights>Copyright Mary Ann Liebert, Inc. Jul 2016</rights><rights>Copyright 2016, Mary Ann Liebert, Inc. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-ba3f9d0f36c97b1d0d72f856c67f9ec95bad5237c41f833748581e07773257ca3</citedby><cites>FETCH-LOGICAL-c511t-ba3f9d0f36c97b1d0d72f856c67f9ec95bad5237c41f833748581e07773257ca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27197548$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Karumuthil-Melethil, Subha</creatorcontrib><creatorcontrib>Nagabhushan Kalburgi, Sahana</creatorcontrib><creatorcontrib>Thompson, Patrick</creatorcontrib><creatorcontrib>Tropak, Michael</creatorcontrib><creatorcontrib>Kaytor, Michael D</creatorcontrib><creatorcontrib>Keimel, John G</creatorcontrib><creatorcontrib>Mark, Brian L</creatorcontrib><creatorcontrib>Mahuran, Don</creatorcontrib><creatorcontrib>Walia, Jagdeep S</creatorcontrib><creatorcontrib>Gray, Steven J</creatorcontrib><title>Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), 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 α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM 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 in vivo 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 GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system.</description><subject>Adeno-associated virus</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Brain</subject><subject>Central nervous system</subject><subject>Dependovirus - genetics</subject><subject>Design</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>G(M2) Ganglioside - metabolism</subject><subject>Ganglioside GM2</subject><subject>Gangliosidosis</subject><subject>Gene transfer</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors - administration & dosage</subject><subject>Genomes</subject><subject>Hexosaminidases - genetics</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Medical treatment</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Neonates</subject><subject>Nervous system</subject><subject>Neurodegenerative diseases</subject><subject>Packaging</subject><subject>Proteins</subject><subject>Spinal cord</subject><subject>Substrates</subject><subject>Tay-Sachs disease</subject><subject>Tay-Sachs Disease - genetics</subject><subject>Tay-Sachs Disease - therapy</subject><subject>Viruses</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkktv1DAUhS0EoqWwY40ssemCDH7GyQZpNG0pUgWLDrO1HOd6xlViD3ZS0X_Az65HLRWwYuUr-dO5j3MQekvJgpKm_bibxwUjtF4Qyp-hYyqlqpRg7HmpieAV4YIdoVc535BCyFq9REdM0VZJ0RyjX1_jLQx4A3aKCZ9B9tuATejxJfyM2Yw--N5kwBuTvAkTPg-mG3zY4msYXLWK436AEcJk0h1e9hBitcw5Wm8m6PHGpzljV4SnHeB1AjMdWBwdXpu76trYXcZnPkPp8Bq9cGbI8ObxPUHfL87Xq8vq6tvnL6vlVWUlpVPVGe7anjhe21Z1tCe9Yq6Rta2Va8G2sjO9ZFxZQV3DuRKNbCgQpRRnUlnDT9CnB9393I3Q2zJPMoPeJz-WHXQ0Xv_9E_xOb-Otlly0jNMicPookOKPGfKkR58tDIMJEOesadNQJVrB-H-gRKqaE9EW9P0_6E2cUyiX0Ky4RhWV6kB9eKBsijkncE9zU6IPadAlDfqQBl28Lvi7P3d9gn_bz-8BgIGxiA</recordid><startdate>201607</startdate><enddate>201607</enddate><creator>Karumuthil-Melethil, Subha</creator><creator>Nagabhushan Kalburgi, Sahana</creator><creator>Thompson, Patrick</creator><creator>Tropak, Michael</creator><creator>Kaytor, Michael D</creator><creator>Keimel, John G</creator><creator>Mark, Brian L</creator><creator>Mahuran, Don</creator><creator>Walia, Jagdeep S</creator><creator>Gray, Steven J</creator><general>Mary Ann Liebert, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201607</creationdate><title>Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease</title><author>Karumuthil-Melethil, Subha ; Nagabhushan Kalburgi, Sahana ; Thompson, Patrick ; Tropak, Michael ; Kaytor, Michael D ; Keimel, John G ; Mark, Brian L ; Mahuran, Don ; Walia, Jagdeep S ; Gray, Steven J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-ba3f9d0f36c97b1d0d72f856c67f9ec95bad5237c41f833748581e07773257ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adeno-associated virus</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Brain</topic><topic>Central nervous system</topic><topic>Dependovirus - genetics</topic><topic>Design</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>G(M2) Ganglioside - metabolism</topic><topic>Ganglioside GM2</topic><topic>Gangliosidosis</topic><topic>Gene transfer</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors - administration & dosage</topic><topic>Genomes</topic><topic>Hexosaminidases - genetics</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Medical treatment</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Neonates</topic><topic>Nervous system</topic><topic>Neurodegenerative diseases</topic><topic>Packaging</topic><topic>Proteins</topic><topic>Spinal cord</topic><topic>Substrates</topic><topic>Tay-Sachs disease</topic><topic>Tay-Sachs Disease - genetics</topic><topic>Tay-Sachs Disease - therapy</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Karumuthil-Melethil, Subha</creatorcontrib><creatorcontrib>Nagabhushan Kalburgi, Sahana</creatorcontrib><creatorcontrib>Thompson, Patrick</creatorcontrib><creatorcontrib>Tropak, Michael</creatorcontrib><creatorcontrib>Kaytor, Michael D</creatorcontrib><creatorcontrib>Keimel, John G</creatorcontrib><creatorcontrib>Mark, Brian L</creatorcontrib><creatorcontrib>Mahuran, Don</creatorcontrib><creatorcontrib>Walia, Jagdeep S</creatorcontrib><creatorcontrib>Gray, Steven J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Karumuthil-Melethil, Subha</au><au>Nagabhushan Kalburgi, Sahana</au><au>Thompson, Patrick</au><au>Tropak, Michael</au><au>Kaytor, Michael D</au><au>Keimel, John G</au><au>Mark, Brian L</au><au>Mahuran, Don</au><au>Walia, Jagdeep S</au><au>Gray, Steven J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>2016-07</date><risdate>2016</risdate><volume>27</volume><issue>7</issue><spage>509</spage><epage>521</epage><pages>509-521</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><abstract>GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), 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 α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM 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 in vivo 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 GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>27197548</pmid><doi>10.1089/hum.2016.013</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1043-0342 |
ispartof | Human gene therapy, 2016-07, Vol.27 (7), p.509-521 |
issn | 1043-0342 1557-7422 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5349231 |
source | MEDLINE; Alma/SFX Local Collection |
subjects | Adeno-associated virus Animals Animals, Newborn Brain Central nervous system Dependovirus - genetics Design Disease Disease Models, Animal Female G(M2) Ganglioside - metabolism Ganglioside GM2 Gangliosidosis Gene transfer Genetic Therapy Genetic Vectors - administration & dosage Genomes Hexosaminidases - genetics Liver Liver - metabolism Medical treatment Mice Mice, Inbred C57BL Mutation Mutation - genetics Neonates Nervous system Neurodegenerative diseases Packaging Proteins Spinal cord Substrates Tay-Sachs disease Tay-Sachs Disease - genetics Tay-Sachs Disease - therapy Viruses |
title | Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T23%3A14%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Novel%20Vector%20Design%20and%20Hexosaminidase%20Variant%20Enabling%20Self-Complementary%20Adeno-Associated%20Virus%20for%20the%20Treatment%20of%20Tay-Sachs%20Disease&rft.jtitle=Human%20gene%20therapy&rft.au=Karumuthil-Melethil,%20Subha&rft.date=2016-07&rft.volume=27&rft.issue=7&rft.spage=509&rft.epage=521&rft.pages=509-521&rft.issn=1043-0342&rft.eissn=1557-7422&rft_id=info:doi/10.1089/hum.2016.013&rft_dat=%3Cproquest_pubme%3E1805763049%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2135171579&rft_id=info:pmid/27197548&rfr_iscdi=true |