Intravitreous anti-raf-1 kinase antisense oligonucleotide as an angioinhibitory agent in porcine preretinal neovascularization

Danis, Ronald P.; Criswell, Mark H.; Örge, Faruk; Wancewicz, Edward V.; Stecker, K.; Henry, Scott P.; Monia, Brett P.

doi:10.1076/ceyr.26.1.45.14252

Cited by 24 publications

(16 citation statements)

References 24 publications

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“…To date only a scarce dataset on the use of the minipig in SSO safety assessment is publicly available. In single studies, SSOs were administered either intradermally (Cai et al , 2012), intravitreally (Danis et al , 2003), subcutaneously (Iyer et al , 2002), or topically (Mehta et al , 2000). With the recent sequencing of its genome (Heckel et al , 2015; Vamathevan et al , 2013), the minipig may now enable the design of cross-species reactive SSOs and the assessment of pharmacology-related adverse effects.…”

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confidence: 99%

The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides

et al. 2017

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Non-human primates (NHPs) are currently considered to be the non-rodent species of choice for the preclinical safety assessment of single-stranded oligonucleotide (SSO) drugs. We evaluated minipigs as a potential alternative to NHPs to test the safety of this class of compounds. Four different phosphorothioated locked nucleic acid-based SSOs (3 antisense and 1 anti-miR), all with known safety profiles, were administered to minipigs using similar study designs and read-outs as in earlier NHP studies with the same compounds. The studies included toxicokinetic investigations, in-life monitoring, clinical and anatomic pathology. In the minipig, we demonstrated target engagement by the SSOs where relevant, and a similar toxicokinetic behavior in plasma, kidney, and liver when compared with NHPs. Clinical tolerability was similar between minipig and NHPs. For the first time, we showed similar and dose-dependent effects on the coagulation and complement cascade after intravenous dosing similar to those observed in NHPs. Similar to NHPs, morphological changes were seen in proximal tubular epithelial cells of the kidney, Kupffer cells, hepatocytes, and lymph nodes. Minipigs appeared more sensitive to the high-dose kidney toxicity of most of the selected SSOs than NHPs. No new target organ or off-target toxicities were identified in the minipig. The minipig did not predict the clinical features of human injection site reactions better than the NHPs, but histopathological similarities were observed between minipigs and NHPs. We conclude that there is no impediment, as default, to the use of minipigs as the non-rodent species in SSO candidate non-clinical safety packages.

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confidence: 99%

The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides

et al. 2017

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“…iCo-007 is a second generation ASO targeting c-Raf kinase that has been discovered by ISIS Pharmaceuticals Inc. (Carlsbad, California, USA). In pig models of branch vein occlusion and mouse models of laser induced choroidal neovascularization the ASO caused inhibition of c-Raf expression and improvement in the neovascularization severity score (Danis et al 2003). iCo-007 was licensed to iCo Therapeutics Inc. (Vancouver, British Columbia, Canada) in 2005 and since then it has been in an open label, dose escalating Phase I clinical trial in patients with DME.…”

Section: Ico-007 For Diabetic Retinopathy and Diabetic Macular Edemamentioning

confidence: 99%

Nanocarriers of Antisense Oligonucleotides in Diabetes

Rapini

Bottini

Bottini³

2012

Nanotechnology and Nanomedicine in Diabetes

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Antisense oligonucleotides are short strands of deoxyribonucleotides that are complementary to specifi c encoding mRNA sequences and can block gene expression. Their potential use as therapeutic and gene validation tools has elicited great interest. However, poor intracellular delivery into several tissues in living animals currently limits the range of in vivo applications of antisense oligonucleotides. Innovative solutions to this problem are coming from nanomedicine, a discipline recently born from the marriage of nanotechnology and medicine. Through the use of nanotechnology-derived composites (nanocarriers), nanomedicine helps traditional drugs to avoid the body's defenses that the drug encounters following its systemic administration. In this chapter we will describe diabetes-relevant applications of nanocarriers as Nanocarriers of Antisense Oligonucleotides in Diabetes 65delivery systems for antisense oligonucleotides. We divided the chapter in two sections. In the fi rst section we will 1) describe the modes of action of antisense oligonucleotides and the chemical modifi cations that have been developed to ameliorate resistance to nucleases, enhance affi nity and potency, and reduce toxicity; 2) the biological barriers encountered by the antisense oligonucleotides following their systemic administration; 3) the arsenal of solutions that nanomedicine can offer to enable the safe delivery of antisense oligonucleotides to the target site. In the second section, we will review the antisense oligonucleotides and delivery systems that have been developed as novel therapeutic weapons against diabetes. This includes research from our laboratory focusing on achieving targeted delivery of antisense oligonucleotides into T cells for therapy of Type 1 Diabetes.

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“…RTK inhibition is thus a potential therapeutic to block VEGF signaling pathway intracellularly. iCo-007, an antisense oligonucleotide against the VEGF downstream pathway mediator, C-raf kinase, was demonstrated to inhibit ocular NV in animal models [Danis et al, 2003]. It is currently being clinically evaluated in AMD patients with CNV, with potential extended use for treating DR and DME.…”

Section: Anti-vegf Therapeuticsmentioning

confidence: 99%

Diabetic retinopathy: a review

Chu

Ali

2008

Drug Development Research

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Diabetic retinopathy is a progressive disease elicited by chronic exposure to high blood glucose, e.g., hyperglycemia and is generally recognized as a vascular disease like other diabetesrelated diseases. Although the pathogenesis of diabetic retinopathy has not been clearly elucidated, numerous drugs have been developed based on the current understanding of the complicated and intricate biochemical and pathophysiological aspects of the disease. Current therapy for diabetic retinopathy includes laser photocoagulation, surgery, and metabolic control. Future therapies for diabetic retinopathy are based on the pathophysiology of the disease, such as anti-VEGF, anti-angiogenesis, and anti-inflammatory and anti-extracellular matrix pathways. Several clinical trials are ongoing for diabetic macular edema using drug delivery routes including intravitreal injections, subtenon injections and intravenous injection, topical drops, and intravitreal implants. Drug Dev Res 69:1-14, 2008.

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Intravitreous anti-raf-1 kinase antisense oligonucleotide as an angioinhibitory agent in porcine preretinal neovascularization

Cited by 24 publications

References 24 publications

The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides

The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides

Nanocarriers of Antisense Oligonucleotides in Diabetes

Diabetic retinopathy: a review

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