A High Dose of IMT504, the PyNTTTTGT Prototype Immunostimulatory Oligonucleotide, Does Not Alter Embryonic Development in Rats

Hernando-Insúa, Andrés; Rodríguez, Juan Manuel; Elı́as, Fernanda; Fló, Juan; López, Ricardo; Franco, Raúl; Lago, Néstor; Zorzopulos, Jorge; Montaner, Alejandro D.

doi:10.1089/oli.2009.0206

Cited by 9 publications

(6 citation statements)

References 13 publications

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“…Furthermore, in preclinical toxicity studies, we demonstrated that IMT504 is a very safe drug (17,23). We are presently validating the effects of IMT504 in NOD mice, a spontaneous model of T1D.…”

Section: (46) Demonstrated Increasedmentioning

confidence: 71%

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Bianchi

Hernado-Insúa

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Ϫ1 ·day Ϫ1 ip for 5 consecutive days). We determined blood glucose, glucose tolerance, serum insulin, islet morphology, islet infiltration, serum cytokines, progenitor cell markers, immunomodulatory proteins, proliferation, apoptosis, and islet gene expression. IMT504 reduced glycemia, induced ␤-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased ␤-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, and increased serum tumor necrosis factor and interleukin-6 (IL-6). IMT504 affected islet gene expression; preproinsulin-2, proglucagon, somatostatin, nestin, regenerating gene-1, and C-X-C motif ligand-1 cytokine (Cxcl1) increased in islets from diabetic mice and were decreased by IMT504. IMT504 downregulated platelet endothelial cell adhesion molecule-1 (Pecam1) in islets from control and diabetic mice, whereas it increased regenerating gene-2 (Reg2) in islets of diabetic mice. The IMT504-induced increase in IL-6 and islet IDO expression and decreased islet Pecam1 and Cxcl1 mRNA expression could participate in keeping leukocyte infiltration at bay, whereas upregulation of Reg2 may mediate ␤-cell regeneration. We conclude that IMT504 effectively reversed immunodependent diabetes in mice. Corroboration of these effects in a model of autoimmune diabetes more similar to human T1D could provide promising results for the treatment of this disease.

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Section: (46) Demonstrated Increasedmentioning

confidence: 71%

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Bianchi

Hernado-Insúa

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Moreover, because IMT504 has good thermal stability, extreme conditions of transport and storage are not necessary. Finally, IMT504 preclinical toxicity studies performed in several animal species, including non-human primates, indicate that IMT504 is a very safe drug with few secondary effects that are well-tolerated and within the therapeutic range of this agent[364,365]. …”

Section: Practical Considerations Regarding the Prospective Clinical mentioning

confidence: 99%

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

Zorzopulos¹,

Opal²,

Hernando-Insúa³

et al. 2017

WJSC

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The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.

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“…Once a lead vaccine candidate is identified, animal models are used to evaluate its safety, immunogenicity, pharmacokinetics and efficacy. Many species, including mouse (Oda et al, 1983;Paoletti et al, 2000;Abram et al, 2003;Chan et al, 2010;Rahman et al, 2010;Monney et al, 2012;Pazos et al, 2012a, b), rat Weisman, 1989, 1990;Zenner et al, 1993;Hernando-Insua et al, 2010;Kim et al, 2011), hamster (Freyre et al, 2012), guinea pig (Harrison et al, 1995;Bourne et al, 2001;Schleiss et al, 2007Schleiss et al, , 2013Schleiss et al, , 2014Leviton et al, 2013), rabbit (Wessels et al, 1990(Wessels et al, , 1993Barrow, 2012;Barrow andAllais, 2013), sheep (Perez-Sancho et al, 2014), pig (Elahi et al, 2006) and non-human primates (Paoletti et al, 2000;Barry et al, 2006;Warfel et al, 2014), have been used.…”

Section: General Guidelinesmentioning

confidence: 99%

Maternal vaccination: moving the science forward

Faucette

Unger

Gonik

et al. 2014

Human Reproduction Update

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To tackle the scientific challenges of maternal vaccination and to provide the public with informed vaccination choices, scientists and clinicians in different disciplines must work closely and have a mechanistic understanding of the systemic, reproductive and mammary mucosal immune responses to vaccines. The use of animal models should be coupled with human studies in an iterative manner for maternal vaccine experimentation, evaluation and optimization. Systems biology approaches should be adopted to improve the speed, accuracy and safety of maternal vaccine targeting.

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A High Dose of IMT504, the PyNTTTTGT Prototype Immunostimulatory Oligonucleotide, Does Not Alter Embryonic Development in Rats

Cited by 9 publications

References 13 publications

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

Maternal vaccination: moving the science forward

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