Renal uptake and tolerability of a 2′-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey

Henry, Scott P.; Johnson, Mark D.; Zanardi, Thomas; Fey, Robert; Auyeung, Diana J.; Lappin, Patrick B.; Levin, Arthur A.

doi:10.1016/j.tox.2012.06.005

Cited by 48 publications

(40 citation statements)

References 16 publications

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“…This is supported by the observed elevated levels of KIM1, aGST, and NAG, all markers known in animal models to increase in response to different tubulo-toxic agents (Feinfeld et al, 1986;Hoffmann et al, 2010;Vaidya et al, 2010;Ouchi et al, 2012;Swain et al, 2012 ). Accumulation of antisense oligonucleotides occurs in proximal tubular cells as basophilic granules (Monteith et al, 1999;Henry et al, 2012), and this was indeed seen also in animal studies with ISIS 388626 . In primates, tubular accumulation of oligonucleotides is usually not associated with renal toxicity and tubular functional changes, unless extremely high doses are used (Monteith et al, 1999;Henry et al, 2012;Zanardi et al, 2012 ).…”

Section: Discussionmentioning

confidence: 54%

“…Accumulation of antisense oligonucleotides occurs in proximal tubular cells as basophilic granules (Monteith et al, 1999;Henry et al, 2012), and this was indeed seen also in animal studies with ISIS 388626 . In primates, tubular accumulation of oligonucleotides is usually not associated with renal toxicity and tubular functional changes, unless extremely high doses are used (Monteith et al, 1999;Henry et al, 2012;Zanardi et al, 2012 ). In accordance, these compounds are not associated with adverse renal effects in humans during subsequent clinical investigations (Kastelein et al, 2006;van Dongen et al, 2015).…”

Section: Discussionmentioning

confidence: 66%

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Renal Effects of Antisense-Mediated Inhibition of SGLT2

Meer

Moerland

Dongen

et al. 2016

J Pharmacol Exp Ther

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ISIS 388626 is an antisense sodium-glucose cotransporter 2 (SGLT2) inhibitor designed to treat type 2 diabetes mellitus by induction of glucosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100, and 200 mg of ISIS 388626 in humans. ISIS 388626 increased 24-hour urinary glucose excretion dose dependently with 508.9 6 781.45 mg/day in the 100-mg and 1299.8 6 1833.4 mg/day in the 200-mg cohort, versus 88.7 6 259.29 mg/day in the placebo group. ISIS 388626 induced a reversible increase in serum creatinine, with the largest effect after eight doses of ISIS 388626 (200 mg; 0.38 6 0.089 mg/dl; 44% increase over baseline). Three subjects were discontinued as a result of creatinine increases. The renal clearance test revealed no indications for impairment of glomerular filtration or renal perfusion. The creatinine increases were accompanied by a rise in the levels of urinary renal damage markers [b-2-microglobulin (B2M), total protein, kidney injury molecule (KIM1), a-glutathione S-transferase (aGST),Other treatmentrelated adverse events included mild injection site reactions occurring in 8-19% of the subjects. In conclusion, ISIS 388626 treatment induced glucosuria at a dose level of 200 mg/week. This intended pharmacological effect was small, amounting to approximately 1% of the total amount of filtered glucose. Changes in serum and urinary markers were indicative of transient renal dysfunction, most probably of tubular origin. Whether the glucosuria is caused by specific SGLT2 inhibition or general tubular dysfunction or a combination remains uncertain.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 66%

Renal Effects of Antisense-Mediated Inhibition of SGLT2

Meer

Moerland

Dongen

et al. 2016

J Pharmacol Exp Ther

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“…Synthetic PTP1B inhibitor and therapy of Type 2 diabetes: Recent years, many pharmaceutical companies have developed various PTP1B inhibitors as drug candidates for therapy of Type 2 diabetes in clinical trials, including ertiprotafib, ISIS 113715, ISIS-PTP1BRx, and trodusquemine [30]. In addition, some new synthetic PTP1B inhibitors were reported such as Thiazolidinediones, Benzofuran and benzothiophene biphenyls, Vanadium complexes and Amino benzoic acid.…”

Section: Ptp1b Inhibitors and Therapy Of Type 2 Diabetesmentioning

confidence: 99%

Type 2 Diabetes Mellitus and Protein-Tyrosine Phosphatase 1B1

Zou¹

2016

JDMDC

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Diabetes is one of the common metabolic diseases, mainly divided into two types, type 1 diabetes mellitus and type 2 diabetes mellitus. Insulin resistance is the main performance of type 2 diabetes mellitus which are relative to some gene mutation, genetics, obesity and so on. Protein-tyrosine phosphatase 1B (PTP1B) plays an important role as a negative regulator in insulin signaling pathways that are implicated in metabolic diseases such as obesity and type 2 diabetes. Many evidences from clinical and basical reseach shows that the high expression of PTP1B induces insulin resistance and PTP1B is an effective target for the treatment of type 2 diabetes mellitus. In this review, we briefly introduce composition of PTP1B, and then examine the role of PTP1B in insulin signaling of type 2 diabets mellitus. Finally, we highlight the recent research progress of PTP1B inhibitors used in therapy of type 2 diabetes mellitus. medications such as oxidation, nitrosyaltion, sulfyhydration, sumoylation, phosphorylation and proteolytic cleavage. The diverse modifications illustrated the dynamic regulation of this enzyme and its ability to modulate numerous signaling pathways likely in a cell/tissue-and stimulus-dependent manner, with high specificity and precision. PTP1B, as a potential target for type2 diabetes and obesity, have expanded out of PTP1B gene cDNA span [11]. At the same time, the molecular dynamics studies of interaction between PTP1B and its inhibitors are also going on [12], all which lay a foundation for screening specific PTP1B inhibitors. Keywords: The role of PTP1B in insulin signaling of type 2 diabetes mellitusThe pathogenesis of type 2 diabetes are associated with gene mutation, heredity, obesity and other factors, which main performance is insulin resistance. Dysfunction of pancreatic β cells is one of basic processes and characteristic of the pathogenesis. The increased prevalence of this disease highlights the urgent need to elucidate the underlying molecular mechanisms to aid in therapeutic intervention. Insulin secreted from pancreatic β cells acts as a major regulator of glucose homeostasis through a complex and integrated signaling network. Insulin receptor is a kind of transmembrane glycoprotein complex molecules, consisting of two alpha and beta subunits by three disulfide bond connection, among which the alpha subunits locate in the lateral of the cell and beta subunits are across the cell membrane. Insulin binding alpha subunits of the receptor induced phosphorylation of tyrosine residues and protein tyrosine kinase (PTK) of beta subunits, and resulted in a series of phosphorylation and dephosphorylation cascade reactions including mitogen-activated protein kinases (MAPK) and PI3K/Akt signal pathways to regulate metabolism. Whereas, when the concentration of insulin is beyond the physiological concentration (hyperinsulinemia), insulin promoted cell proliferation and developments, which may due to the combination of insulin with insulin-like growth factor 1 receptor (IGF-1R) or insulin-...

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“…One challenge associated with the systemic administration of oligonucleotides formulated in saline is their ability to accumulate and induce histological changes in the kidneys. 36,37 It is not clear at this time whether the histological changes observed after chronic administration of engineered microRNA therapeutics will be associated with loss of renal function in humans. Injection site reactions and the histological changes induced by oligonucleotides in the kidney may be driven in part by immune stimulation 37 and, if so, the ability to design new chemically modified engineered therapeutics with minimal pro-inflammatory potential may limit both of these concerns.…”

Section: Saline Formulationmentioning

confidence: 99%

Engineered microRNA therapeutics

Gibson

2014

J R Coll Physicians Edinb

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Renal uptake and tolerability of a 2′-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey

Cited by 48 publications

References 16 publications

Renal Effects of Antisense-Mediated Inhibition of SGLT2

Renal Effects of Antisense-Mediated Inhibition of SGLT2

Type 2 Diabetes Mellitus and Protein-Tyrosine Phosphatase 1B1

Engineered microRNA therapeutics

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