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.
Highlights
This study demonstrated that the scAAV9-HEXM gene therapy treatment initiated a T
The delivery of scAAV9-HEXM induced T cells that responded to the HexM PEPscreen® library, and produced high levels of anti-HexM antibodies in the sera of the Tay–Sachs Disease (TSD) mice, and elevated levels in the sera of Sandhoff Disease (SD) mice
A high antibody response to purified HexM protein was observed in Het and KO SD mice in this study, when given in combination with adjuvant (Figure 5)
Summary
GM2 gangliosidoses are a group of inherited lysosomal storage diseases, characterized by the toxic accumulation of GM2 gangliosides in the brain. This is the result of a deficiency of the β-hexosaminidase A (HexA) enzyme involved in the catabolism of these lipids [1]. Mutations in either of these genes can produce a HexA deficiency. Tay–Sachs Disease (TSD) results from a deficient α-subunit [3]; a deficient β-subunit leads to Sandhoff Disease (SD) [1]. Both TSD and SD have very similar clinical phenotypes. Between three to five months of age, patients with the infantile-onset form of these diseases typically show signs of impaired motor function, 4.0/)
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