Oligonucleotide IMT504 reduces neuropathic pain after peripheral nerve injury

Coronel, Marı́a Florencia; Hernando-Insúa, Andrés; Rodríguez, Juan Manuel; Elı́as, Fernanda; Chasseing, Norma Alejandra; Montaner, Alejandro D.; Villar, Marcelo J.

doi:10.1016/j.neulet.2008.07.045

Cited by 19 publications

(17 citation statements)

References 30 publications

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“…These effects include in vitro activation, proliferation, and expression of costimulatory molecules on B cells (Elías et al, 2003;Rodriguez et al, 2006a); immune modulatory effect on mice, rats, and primates when combined with a variety of antigens Montaner et al, 2011Montaner et al, , 2012Gan et al, 2009) Statistically significant differences as compared with control (0 mg/kg/day). *p < 0.05; **p < 0.02. improvement of tissue damage or disease in animal models (Rodriguez et al, 2006b;Hernando-Insúa et al, 2007;Coronel et al, 2008;Bianchi et al, 2010). All of these studies contributed to the dose selection for the present non-clinical studies.…”

Section: Pharmacological Effectmentioning

confidence: 96%

“…Also, IMT504, but not CpG ODNs, increases the number of adult mesenchymal stromal cells with multipotent differentiation capacity in vitro and in vivo (Hernando-Insúa et al, 2007). We have also found that treatment with IMT504 causes significant improvements in animal models of bone injury (Hernando-Insúa et al, 2007), neuropathic pain (Coronel et al, 2008), and type 1 diabetes (Bianchi et al, 2010). Furthermore, in human B cells from patients with chronic lymphocytic leukemia, IMT504 induces an immunogenic phenotype (up-regulation of CD25, CD40, CD80, and CD86 surface molecules) and stimulates apoptosis in vitro (Rodriguez et al, 2006b).…”

Section: Introductionmentioning

confidence: 93%

“…Taking into consideration the pharmacological effect described in tissue regeneration models (Hernando-Insúa et al, 2007;Coronel et al, 2008;Bianchi et al, 2010), the femoral bone, peripheral sciatic nerve, and pancreas of rats from the repeated-dose IV toxicity assay (0.35 and 3.5 mg/kg/day) were studied. Organ weight and gross pathology from samples taken at weeks 6 and 12were examined.…”

Section: Examination Of Target Organsmentioning

confidence: 99%

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Non-Clinical Safety Studies of IMT504, a Unique Non-CpG Oligonucleotide

Franco

Rodríguez²,

Elı́as

et al. 2014

Nucleic Acid Therapeutics

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IMT504 is a non-CpG 24-mer oligodeoxynucleotide (ODN) with immunomodulatory as well as tissue repair activity. IMT504 has been previously proven to be effective in animal models of vaccine potency, chronic lymphocytic leukemia, tissue regeneration, and sepsis. Here, we assessed the safety, including pharmacokinetics and toxicity studies in rats and monkeys, of IMT504 in a single-or repeated-dose administration by the subcutaneous (SC) or intravenous (IV) routes. In rats, the maximum tolerated dose was determined to be 50 mg/ kg when administered SC. Adverse effects at 50 mg/kg were mild and reversible liver injury, revealed as lobular inflammation, focal necrosis, and small changes in the transaminase profile. Dose-dependent splenomegaly and lymphoid hyperplasia, most probably associated with immune stimulation, were commonly observed. Rats and monkeys were also IV injected with a single dose of 10 or 3.5 mg/kg, and no adverse effects were observed. Rats injected IV with 10 mg/kg showed a transient increase in spleen weight, together with a slight increase in the marginal zone of the white pulp and in leukocyte count 2 days post-administration. In monkeys, this dosage caused slight changes in total serum complement and leukocyte count on day 14. No adverse effects were observed at 3.5 mg/kg IV in rats or monkeys. Therefore, this dose was defined as the ''no observed adverse effect level'' for this route. Furthermore, repeated-dose toxicity studies were performed in these species using 3.5 or 0.35 mg/kg/day IV for 6 weeks. A transient increase in the spleen and liver weight was observed at 3.5 mg/kg/day only in female rats. No changes in clotting time and activation of the alternative complement pathway were observed. The toxicity profile of IMT504 herein reported suggests a dose range in which IMT504 can be used safely in clinical trials.

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Section: Pharmacological Effectmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 93%

Section: Examination Of Target Organsmentioning

confidence: 99%

See 1 more Smart Citation

Non-Clinical Safety Studies of IMT504, a Unique Non-CpG Oligonucleotide

Franco

Rodríguez²,

Elı́as

et al. 2014

Nucleic Acid Therapeutics

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“…MSC transplantation has proven to be effective for the treatment of neuropathic pain in several preclinical studies[335-342]. In addition, parenteral treatment with IMT504 has been shown to ameliorate neuropathic pain in a rat model of peripheral nerve lesion even when administered several days after nerve injury[343] (Figure 2). …”

Section: Immunomodulatory Oligonucleotide Imt504 and Inflammatory Dismentioning

confidence: 99%

“…It is noticeable that the administration of either IMT504 or MSCs prevents the development of allodynia. Experimental details are described in Coronel et al[343]. MSC: Mesenchymal stem cell.…”

Section: Immunomodulatory Oligonucleotide Imt504 and Inflammatory Dismentioning

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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