DNA-Encoded Glutamine Synthetase Enzyme as Ammonia-Lowering Therapeutic for Hyperammonemia

Khoshnejad, Makan; Dia, Yaya; Patel, Ami; Xu, Ziyang; Zhu, Xizhou; Yun, Kun; Wojtak, Krzysztof; Qureshi, Rehman; Humeau, Laurent; Muthumani, Kar; Weiner, David B.

doi:10.1089/nat.2020.0886

Cited by 3 publications

(3 citation statements)

References 40 publications

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“…Remarkably, a decline in arterial ammonia was observed in AHF mice subsequent to MSCs transplantation, indicating that MSCs predominantly address hyperammonemia by enhancing Gln synthesis and restraining Gln decomposition. This finding is consistent with previous research indicating that inhibiting Gln decomposition or promoting Gln synthesis can effectively mitigate hyperammonemia 14,24 . It is worth noting, though, that the precise mechanisms by which MSCs regulate Gln metabolism remain relatively underexplored in the current scientific discourse.…”

Section: Discussionsupporting

confidence: 93%

Mesenchymal stromal cells ameliorate hyperammonemia via IGF1-IGF1R- GLS2 axis inhibiting glutaminolysis in acute hepatic failure

Cheng,

Shi,

et al. 2023

Preprint

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Hyperammonemia is a pernicious and severe consequence of acute hepatic failure (AHF). While prior research suggested the potential of mesenchymal stromal cells (MSCs) in reducing blood ammonia levels, the underlying molecular mechanism remains unclear. This study utilized a AHF mouse model to investigate the impact of MSCs on hyperammonemia and its mechanism. The study showed that CCL4-induced ALF mice suffered from hyperammonemia. MSCs effectively reduce arterial ammonia levels by downregulating glutaminase2 (Gls2) and upregulating glutamine synthetase (GS), rather than through urea cycle. RFP-labeled MSCs were observed in hepatic sinusoid and co-localized with macrophages. Moreover, the MSC treatment group exhibited elevated expression of insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) than the PBS treatment group. Furthermore, Inhibition of the IGF1-IGF1R axis attenuated the ammonia-lowing effect of MSCs. Notably, blocking IGF1-IGF1R axis could affect the MSCs’ inhibition effects on Gls2. The finding indicates that MSCs can mitigate hyperammonemia in AHF mice by suppressing glutaminolysis through IGF1-IGF1R axis, making them a promising resource for treating hyperammonemia in critical conditions.

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Section: Discussionsupporting

confidence: 93%

Mesenchymal stromal cells ameliorate hyperammonemia via IGF1-IGF1R- GLS2 axis inhibiting glutaminolysis in acute hepatic failure

Cheng,

Shi,

et al. 2023

Preprint

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“…39,40 Other strategies to enhance DNA immunotherapy include formulation with adjuvants, such as IL-12, and nanoparticle assembly of the antigen, among others, as recently reported. 27,41,42 As the N-terminal domain of BARF1 can activate anti-apoptotic Bcl-2 expression and bind to M-CSF for immune modulation, domains or fragments of BARF1 that contain immune dominant B cell or T cell epitopes can be investigated for future studies. 14 For immunotherapy in humans, additional important antigens as part of an immune cocktail may be important.…”

Section: Discussionmentioning

confidence: 99%

DNA immunotherapy targeting BARF1 induces potent anti-tumor responses against Epstein-Barr-virus-associated carcinomas

Zhu

Perales‐Puchalt

Wojtak

et al. 2022

Molecular Therapy - Oncolytics

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Latent Epstein-Barr virus (EBV) infection is associated with several types of cancer. Several clinical studies have targeted EBV antigens as immune therapeutic targets with limited efficacy of EBV malignancies, suggesting that additional targets might be important. BamHI-A rightward frame 1 (BARF1) is an EBV antigen that is highly expressed in EBV + nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC). BARF1 antigen can transform human epithelial cells in vivo. BARF1-specific antibodies and cytotoxic T cells were detected in some EBV + NPC patients. However, BARF1 has not been evaluated as an antigen in the context of therapeutic immunization. Its possible importance in this context is unclear. Here, we developed a synthetic-DNA-based expression cassette as immunotherapy targeting BARF1 (pBARF1). Immunization with pBARF1 induced potent antigen-specific humoral and T cell responses in vivo. Immunization with pBARF1 plasmid impacted tumor progression through the induction of CD8 + T cells in novel BARF1 + carcinoma models. Using an in vivo imaging system, we observed that pBARF1immunized animals rapidly cleared cancer cells. We demonstrated that pBARF1 can induce antigen-specific immune responses that can impact cancer progression. Further study of this immune target is likely important as part of therapeutic approaches for EBV + malignancies.

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“…To elucidate the effects of hAQP8 expression on mouse liver, we determined the ammonia levels in plasma after a single dose of ammonia acetate. The ammonia levels were measured in systemic blood after 15 min of ammonia challenge [20]. The plasma ammonia concentration was significantly lower in the AdhAQP8-transduced mice (Figure 2A).…”

Section: Ammonia-derived Ureagenesis In Adhaqp8-transduced Micementioning

confidence: 99%

Adenoviral Transfer of Human Aquaporin-8 Gene to Mouse Liver Improves Ammonia-Derived Ureagenesis

Capiglioni

Capitani

Marrone

et al. 2023

Cells

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We previously reported that, in cultured hepatocytes, mitochondrial aquaporin-8 (AQP8) channels facilitate the conversion of ammonia to urea and that the expression of human AQP8 (hAQP8) enhances ammonia-derived ureagenesis. In this study, we evaluated whether hepatic gene transfer of hAQP8 improves detoxification of ammonia to urea in normal mice as well as in mice with impaired hepatocyte ammonia metabolism. A recombinant adenoviral (Ad) vector encoding hAQP8, AdhAQP8, or a control Ad vector was administered via retrograde infusion into the bile duct of the mice. Hepatocyte mitochondrial expression of hAQP8 was confirmed using confocal immunofluorescence and immunoblotting. The normal hAQP8-transduced mice showed decreased plasma ammonia and increased liver urea. Enhanced ureagenesis was confirmed via the NMR studies assessing the synthesis of 15N-labeled urea from 15N-labeled ammonia. In separate experiments, we made use of the model hepatotoxic agent, thioacetamide, to induce defective hepatic metabolism of ammonia in mice. The adenovirus-mediated mitochondrial expression of hAQP8 was able to restore normal ammonemia and ureagenesis in the liver of the mice. Our data suggest that hAQP8 gene transfer to mouse liver improves detoxification of ammonia to urea. This finding could help better understand and treat disorders with defective hepatic ammonia metabolism.

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DNA-Encoded Glutamine Synthetase Enzyme as Ammonia-Lowering Therapeutic for Hyperammonemia

Cited by 3 publications

References 40 publications

Mesenchymal stromal cells ameliorate hyperammonemia via IGF1-IGF1R- GLS2 axis inhibiting glutaminolysis in acute hepatic failure

Mesenchymal stromal cells ameliorate hyperammonemia via IGF1-IGF1R- GLS2 axis inhibiting glutaminolysis in acute hepatic failure

DNA immunotherapy targeting BARF1 induces potent anti-tumor responses against Epstein-Barr-virus-associated carcinomas

Adenoviral Transfer of Human Aquaporin-8 Gene to Mouse Liver Improves Ammonia-Derived Ureagenesis

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