Gene delivery of albumin binding peptide-interferon-gamma fusion protein with improved pharmacokinetic properties and sustained biological activity

Miyakawa, N; Nishikawa, Makiya; Takahashi, Yuki; Ando, Mitsuru; Misaka, Masayuki; Watanabe, Yoshihiko; Takakura, Yoshinobu

doi:10.1002/jps.23493

Cited by 7 publications

(4 citation statements)

References 29 publications

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“…However, the ability of desHis 1 Pro 4 Glu 9 -glucagon(Lys 12 PAL), and particularly desHis 1 Pro 4 Glu 9 -glucagon, to increase energy expenditure does contrast with this notion, but this may simply highlight the plasticity of signalling pathways involved in energy homeostasis ( Smith et al 2018 ). The slight difference in efficacy between desHis 1 Pro 4 Glu 9 -glucagon and desHis 1 Pro 4 Glu 9 -glucagon(Lys 12 PAL) in terms of indirect calorimetry data could be related to free vs albumin-bound drug, where it is often considered that albumin binding reduces bioactivity of peptides ( Miyakawa et al 2013 ). However, more detailed pharmacokinetic studies, that are outside the scope of the current investigation, would be required to confirm this.…”

Section: Discussionmentioning

confidence: 99%

Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

Lafferty

McShane

Franklin

et al. 2022

Journal of Endocrinology

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Discerning modification to the amino acid sequence of native glucagon can generate specific glucagon receptor (GCGR) antagonists, that include desHis1Pro4Glu9-glucagon and the acylated form desHis1Pro4Glu9(Lys12PAL)-glucagon. In the current study, we have evaluated the metabolic benefits of once daily injection of these peptide-based GCGR antagonists for 18 days in insulin-resistant high fat fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice. Administration of desHis1Pro4Glu9-glucagon moderately (P<0.05) decreased STZ-induced elevations of food intake. Body weight was not different between groups of HFF-STZ mice and both treatment interventions delayed (P<0.05) the onset of hyperglycaemia. The treatments reduced (P<0.05 - P<0.001) circulating and pancreatic glucagon, whilst desHis1Pro4Glu9(Lys12PAL)-glucagon also substantially increased (P<0.001) pancreatic insulin stores. Oral glucose tolerance was appreciably improved (P<0.05) by both antagonists, despite lack of augmentation of glucose-stimulated insulin release. Interestingly, positive effects on intraperitoneal glucose tolerance were less obvious suggesting important beneficial effects on gut function. Metabolic benefits were accompanied by decreased (P<0.05 - P<0.01) locomotor activity and increases (P<0.001) in energy expenditure and respiratory exchange ratio in both treatment groups. In addition, desHis1Pro4Glu9-glucagon increased (P<0.01 - P<0.001) O2 consumption and CO2 production. Together, these data provide further evidence that peptidic GCGR antagonists are effective treatment options for obesity-driven forms of diabetes, even when accompanied by insulin deficiency.

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Section: Discussionmentioning

confidence: 99%

Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

Lafferty

McShane

Franklin

et al. 2022

Journal of Endocrinology

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“…Quantification was conducted in LightCycler ® Nano SW v. 1.1. The primer sequences used were reported earlier [22,23,24,25,26]. The primer sequences were 5′-CACAGGTATCCTCAGAGCT-3′ and 5′-TGTAGTCCGTGGTGGCCAC-3′ for neutrophil gelatinase-associated lipocalin (NGAL), 5′-AGGCCTGACATCTTCTGCAA-3′ and 5′-TCTGACATGGCAGCCATTGT-3′ for IL-18, 5′-GGACCACGGAGCCAATTTC-3′ and 5′-CTCGGAGACATTAGAGAACAATGC-3′ for intercellular adhesion molecule-1 (ICAM-1), 5′-ACAAAACGATTGCTCAAATCGG-3′ and 5′-CGCGTTTAGTGGGCTGTCTATC-3′ for vascular cell adhesion molecule-1 (VCAM-1), and 5′-CATCCGTAAAGACCTCTATGC-3′ and 5′-ATGGAGCCACCGATCCACA-3′ for β-actin (Actb).…”

Section: Methodsmentioning

confidence: 99%

l-Cysteine and l-Serine Modified Dendrimer with Multiple Reduced Thiols as a Kidney-Targeting Reactive Oxygen Species Scavenger to Prevent Renal Ischemia/Reperfusion Injury

et al. 2018

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l-cysteine (Cys)- and l-serine (Ser)-modified, third-generation polyamidoamine (PAMAM) dendrimer with multiple reduced thiols (Ser-PAMAM-Cys) was synthesized as a kidney-targeting reactive oxygen species (ROS) scavenger to help prevent renal ischemia/reperfusion injury. Ser-PAMAM-Cys effectively scavenged 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and ROS (hydrogen peroxide and hydroxyl radical) in phosphate-buffered saline (PBS). In addition, ~64% of 111In-labeled Ser-PAMAM-Cys accumulated in mouse kidney 3 h after intravenous administration. An in vivo imaging system (IVIS) study indicated that near-infrared fluorescence dye (NIR)-labeled Ser-PAMAM-Cys specifically accumulated in the kidney. In a mouse renal ischemia/reperfusion injury model, increases in the kidney damage markers creatinine (Cre) and blood urea nitrogen (BUN) were significantly inhibited by intravenous Ser-PAMAM-Cys administration. In contrast, Cys injection had no statistically significant effect of preventing Cre or BUN elevation relative to the control. Ser-PAMAM-Cys also effectively downregulated the inflammatory factors NGAL, IL-18, ICAM-1, and VCAM-1 in the renal ischemia/reperfusion injury model. These results indicate that Ser-PAMAM-Cys is a promising kidney-targeting ROS scavenger which could prevent ischemia/reperfusion-induced renal failure.

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“…Ando et al [ 68 ] confirmed these results and demonstrated that a reduced number of CpG motifs in gene constructs resulted in more durable transgene expression. In 2013, Miyakawa et al [ 69 ] designed another plasmid encoding a fusion protein containing IFN-γ and albumin binding protein that could extend the circulating half-life of IFN, retaining 40–50% of biological activity. With the aim of avoiding the systemic side effects related with IFN, Ando et al [ 70 ] designed constructions encoding fusion proteins of IFN and heparin binding domain in order to target the liver.…”

Section: Gene Transfer Applicationsmentioning

confidence: 99%

Translational Advances of Hydrofection by Hydrodynamic Injection

Sendra

Herrero

Aliño

2018

Genes

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Hydrodynamic gene delivery has proven to be a safe and efficient procedure for gene transfer, able to mediate, in murine model, therapeutic levels of proteins encoded by the transfected gene. In different disease models and targeting distinct organs, it has been demonstrated to revert the pathologic symptoms and signs. The therapeutic potential of hydrofection led different groups to work on the clinical translation of the procedure. In order to prevent the hemodynamic side effects derived from the rapid injection of a large volume, the conditions had to be moderated to make them compatible with its use in mid-size animal models such as rat, hamster and rabbit and large animals as dog, pig and primates. Despite the different approaches performed to adapt the conditions of gene delivery, the results obtained in any of these mid-size and large animals have been poorer than those obtained in murine model. Among these different strategies to reduce the volume employed, the most effective one has been to exclude the vasculature of the target organ and inject the solution directly. This procedure has permitted, by catheterization and surgical procedures in large animals, achieving protein expression levels in tissue close to those achieved in gold standard models. These promising results and the possibility of employing these strategies to transfer gene constructs able to edit genes, such as CRISPR, have renewed the clinical interest of this procedure of gene transfer. In order to translate the hydrodynamic gene delivery to human use, it is demanding the standardization of the procedure conditions and the molecular parameters of evaluation in order to be able to compare the results and establish a homogeneous manner of expressing the data obtained, as ‘classic’ drugs.

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Gene delivery of albumin binding peptide-interferon-gamma fusion protein with improved pharmacokinetic properties and sustained biological activity

Cited by 7 publications

References 29 publications

Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

l-Cysteine and l-Serine Modified Dendrimer with Multiple Reduced Thiols as a Kidney-Targeting Reactive Oxygen Species Scavenger to Prevent Renal Ischemia/Reperfusion Injury

Translational Advances of Hydrofection by Hydrodynamic Injection

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