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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy
Jorge Zorzopulos, Steven M Opal, Andrés Hernando-Insúa, Juan M Rodriguez, Fernanda Elías, Juan Fló, Ricardo A López, Norma A Chasseing, Victoria A Lux-Lantos, Maria F Coronel, Raul Franco, Alejandro D Montaner, David L Horn
Jorge Zorzopulos, Juan Fló, Ricardo A López, Raul Franco, Immunotech S.A., Ciudad de Buenos Aires C1440FFX, Argentina
Steven M Opal, Infectious Disease Division, Memorial Hospital of Rhode Island and Alpert Medical School, Providence, RI 02905, United States
Andrés Hernando-Insúa, Juan M Rodriguez, Fernanda Elías, Alejandro D Montaner, Fundación Pablo Cassara, Ciudad Autonoma de Buenos Aires C1440FFX, Argentina
Norma A Chasseing, Maria F Coronel, Vicoria A Lux-Lantos, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Ciudad Autónoma de Buenos Aires C1428ADN, Argentina
Alejandro D Montaner, Instituto de Ciencia y Tecnologıa “Dr. Cesar Milstein”, Fundación Pablo Cassará, Ciudad Autonoma de Buenos Aires C1440FFX, Argentina
David L Horn, David Horn LLC, Doylestown, PA 18902, United States
Author contributions: All authors contributed equally to this paper in conception and design of definite studies, and in analysis, drafting, critical revision, editing, and providing final approval of the version to be published; Zorzopulos J reviewed the literature and wrote the paper.
Conflict-of-interest statement: López RA and Zorzopulos J are shareholders of Immunotech, the company that provided funding for several of the studies partially described in this review; Horn DL is the owner and CEO of David Horn, LLC, which owns all the IMT504 patents [Patents numbers: EP1511845B1. Immunostimulatory oligonucleotides and uses thereof. International application number: PCT/EP2003/005691. International publication number: WO2003/101375. US7943316(B2)]. There are no further patents, products in development, or marketed products to declare. These statements do not alter the authors’ adherence to all the BPG policies on sharing data and material.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Alejandro D Montaner, PhD, Instituto de Ciencia y Tecnologıa “Dr. Cesar Milstein”, Fundación Pablo Cassará, 2453 Saladillo Street, Ciudad Autonoma de Buenos Aires C1440FFX, Argentina.
amontaner@fundacioncassara.org.ar
Telephone: +54-11-41054126-2102
Received: July 12, 2016
Peer-review started: July 13, 2016
First decision: September 2, 2016
Revised: October 28, 2016
Accepted: December 16, 2016
Article in press: December 19, 2016
Published online: March 26, 2017
Processing time: 256 Days and 22.8 Hours
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.
Core tip: Mesenchymal stem cell (MSC) transplant has been demonstrated to be an effective therapy in preclinical studies evaluating a vast diversity of inflammatory conditions. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. In this regard, 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. 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 are likely to benefit from an immunoprotective/immunoregenerative therapy.
