Dataset Information

Investigating Immune Responses to the scAAV9-HEXM Gene Therapy Treatment in Tay-Sachs Disease and Sandhoff Disease Mouse Models.

ABSTRACT: 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-HEXM 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-HEXM 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.

SUBMITTER: Kot S

PROVIDER: S-EPMC8268035 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay-Sachs Disease and Sandhoff Disease Mouse Models.

Kot Shalini S Karumuthil-Melethil Subha S Woodley Evan E Zaric Violeta V Thompson Patrick P Chen Zhilin Z Lykken Erik E Keimel John G JG Kaemmerer William F WF Gray Steven J SJ Walia Jagdeep S JS

International journal of molecular sciences 20210623 13

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 ...[more]

PMID: 34201771

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Project description:GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants in HEXA encoding the α-subunit and Sandhoff disease is caused by variants in HEXB encoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable. We applied diffusion tensor imaging (DTI) and correlational fiber tractography to assess phenotypic differences in these two diseases. 40 DTI scans from 16 Late-Onset GM2 patients (NCT00029965) with either Sandhoff (n = 4), or Tay-Sachs (n = 12) disease. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), and quantitative anisotropy (QA) were calculated in fiber tracts throughout the whole brain, arcuate fasciculus, corpus callosum, and cerebellum. Correlational tractography was also performed to identify fiber tracts with group wide differences in DTI metrics between Tay-Sachs and Sandhoff patients. A linear mixed effects model was used to analyze the differences between Tay-Sachs and Sandhoff patients. Tay-Sachs patients had higher MD in the left cerebellum (p = 0.003703), right cerebellum (p = 0.003435), superior cerebellar peduncle (SCP, p = 0.007332), and vermis (p = 0.01007). Sandhoff patients had higher FA in the left cerebellum (p = 0.005537), right cerebellum (p = 0.01905), SCP (p = 0.02844), and vermis (p = 0.02469). Correlational fiber tractography identified fiber tracts almost exclusively in cerebellar pathways with higher FA and QA, and lower MD, AD, and RD in Sandhoff patients compared to Tay-Sachs patients. Our study shows neurobiological differences between these two related disorders. To our knowledge, this is the first study using correlational tractography in a lysosomal storage disorder demonstrating these differences. This result indicates a greater burden of cerebellar pathology in Tay-Sachs patients compared with Sandoff patients.

Dataset Information

Investigating Immune Responses to the scAAV9-HEXM Gene Therapy Treatment in Tay-Sachs Disease and Sandhoff Disease Mouse Models.

Publications

Investigating Immune Responses to the scAAV9-<i>HEXM</i> Gene Therapy Treatment in Tay-Sachs Disease and Sandhoff Disease Mouse Models.

Similar Datasets

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