Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models
GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Vir...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/6751 |
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doaj-466f52285cfe442f99f9974dfd0081d62021-07-15T15:36:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-01226751675110.3390/ijms22136751Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse ModelsShalini Kot0Subha Karumuthil-Melethil1Evan Woodley2Violeta Zaric3Patrick Thompson4Zhilin Chen5Erik Lykken6John G. Keimel7William F. Kaemmerer8Steven J. Gray9Jagdeep S. Walia10Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, CanadaGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, CanadaGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAMedical Genetics, Department of Pediatrics, Queen’s University, Kingston, ON K7L 2V7, CanadaMedical Genetics, Department of Pediatrics, Queen’s University, Kingston, ON K7L 2V7, CanadaGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USANew Hope Research Foundation, North Oaks, MN 55127, USANew Hope Research Foundation, North Oaks, MN 55127, USAGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, CanadaGM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Viral vector gene transfer is viewed as a potential method of treating these diseases. A recently constructed isoenzyme to HexA, called HexM, has the ability to effectively catabolize GM2 gangliosides in vivo. Previous gene transfer studies have revealed that the scAAV9-<i>HEXM</i> treatment can improve survival in the murine SD model. However, it is speculated that this treatment could elicit an immune response to the carrier capsid and “non-self”-expressed transgene. This study was designed to assess the immunocompetence of TSD and SD mice, and test the immune response to the scAAV9-<i>HEXM</i> gene transfer. HexM vector-treated mice developed a significant anti-HexM T cell response and antibody response. This study confirms that TSD and SD mouse models are immunocompetent, and that gene transfer expression can create an immune response in these mice. These mouse models could be utilized for investigating methods of mitigating immune responses to gene transfer-expressed “non-self” proteins, and potentially improve treatment efficacy.https://www.mdpi.com/1422-0067/22/13/6751GM2gangliosidosisTay-SachsSandhoffscAAV9-<i>HEXM</i>HexM |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Shalini Kot Subha Karumuthil-Melethil Evan Woodley Violeta Zaric Patrick Thompson Zhilin Chen Erik Lykken John G. Keimel William F. Kaemmerer Steven J. Gray Jagdeep S. Walia |
| spellingShingle |
Shalini Kot Subha Karumuthil-Melethil Evan Woodley Violeta Zaric Patrick Thompson Zhilin Chen Erik Lykken John G. Keimel William F. Kaemmerer Steven J. Gray Jagdeep S. Walia Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models International Journal of Molecular Sciences GM2 gangliosidosis Tay-Sachs Sandhoff scAAV9-<i>HEXM</i> HexM |
| author_facet |
Shalini Kot Subha Karumuthil-Melethil Evan Woodley Violeta Zaric Patrick Thompson Zhilin Chen Erik Lykken John G. Keimel William F. Kaemmerer Steven J. Gray Jagdeep S. Walia |
| author_sort |
Shalini Kot |
| title |
Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models |
| title_short |
Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models |
| title_full |
Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models |
| title_fullStr |
Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models |
| title_full_unstemmed |
Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models |
| title_sort |
investigating immune responses to the scaav9-<i>hexm</i> gene therapy treatment in tay–sachs disease and sandhoff disease mouse models |
| publisher |
MDPI AG |
| series |
International Journal of Molecular Sciences |
| issn |
1661-6596 1422-0067 |
| publishDate |
2021-06-01 |
| description |
GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Viral vector gene transfer is viewed as a potential method of treating these diseases. A recently constructed isoenzyme to HexA, called HexM, has the ability to effectively catabolize GM2 gangliosides in vivo. Previous gene transfer studies have revealed that the scAAV9-<i>HEXM</i> treatment can improve survival in the murine SD model. However, it is speculated that this treatment could elicit an immune response to the carrier capsid and “non-self”-expressed transgene. This study was designed to assess the immunocompetence of TSD and SD mice, and test the immune response to the scAAV9-<i>HEXM</i> gene transfer. HexM vector-treated mice developed a significant anti-HexM T cell response and antibody response. This study confirms that TSD and SD mouse models are immunocompetent, and that gene transfer expression can create an immune response in these mice. These mouse models could be utilized for investigating methods of mitigating immune responses to gene transfer-expressed “non-self” proteins, and potentially improve treatment efficacy. |
| topic |
GM2 gangliosidosis Tay-Sachs Sandhoff scAAV9-<i>HEXM</i> HexM |
| url |
https://www.mdpi.com/1422-0067/22/13/6751 |
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