Activation of Innate Immunity by Therapeutic Nucleic Acids.

Ali Bishani,Elena L Chernolovskaya

doi:10.3390/ijms222413360

Abstract

Nucleic acid-based therapeutics have gained increased attention during recent decades because of their wide range of application prospects. Immunostimulatory nucleic acids represent a promising class of potential drugs for the treatment of tumoral and viral diseases due to their low toxicity and stimulation of the body’s own innate immunity by acting on the natural mechanisms of its activation. The repertoire of nucleic acids that directly interact with the components of the immune system is expanding with the improvement of both analytical methods and methods for the synthesis of nucleic acids and their derivatives. Despite the obvious progress in this area, the problem of delivering therapeutic acids to target cells as well as the unresolved issue of achieving a specific therapeutic effect based on activating the mechanism of interferon and anti-inflammatory cytokine synthesis. Minimizing the undesirable effects of excessive secretion of inflammatory cytokines remains an unsolved task. This review examines recent data on the types of immunostimulatory nucleic acids, the receptors interacting with them, and the mechanisms of immunity activation under the action of these molecules. Finally, data on immunostimulatory nucleic acids in ongoing and completed clinical trials will be summarized.

Highlights

Immunotherapy is the treatment of disease through the manipulation of immune responses by either amplification or suppression
When the immunostimulatory effect of SNAs made of ssRNA instead of DNA (Table 1) was studied, the data showed that the SNAs entered both antigen-presenting cells (APCs) and non-APCs and caused a notable and sequence-specific activation of TLR7 and TLR8
The recognition of nucleic acids by the immune system for protection against infection by foreign agents is provided by complex evolutionarily conservative mechanisms, the implementation of which involves numerous sensors with different specificities. Such foreign agents include therapeutic nucleic acids introduced into the body from the outside

Summary

Introduction

Immunotherapy is the treatment of disease through the manipulation of immune responses by either amplification or suppression. The regulatory C-terminal domain of LGP2 binds to the dsRNA binding protein PACT, and this complex inhibits the RIG-Idependent response and activates the MDA5-dependent response This interaction allows the cellular RNA silencing machine to coordinate the innate immune response [45]. For immunostimulatory RNA (isRNA)-based drugs, targeting TLRs 3/7/8 and RLRs such as MDA5 and RIG-I like receptor to induce type-I interferons might be a good idea, since these sensors preferably bind with different RNA molecules. These receptors send signals to synthesize proinflammatory cytokines and their overstimulation might cause side effects such as chronic inflammation. Determining the feasibility of the therapeutic use of these drugs will require an evaluation of the influence of the pro- or anti-inflammatory cytokine profile on the therapeutic effect, as well as on the tolerance and safety of use

Sequence Dependent Immunostimulation

Sequence-Independent Immunostimulation

Signaling Pathways

Nucleic Acid-Based Vaccines and Adjuvants

Conclusions