MicroRNA-based therapeutics in central nervous system injuries

Abstract

Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), are important causes of death and long-term disability worldwide. MicroRNA (miRNA), small non-coding RNA molecules that negatively regulate gene expression, can serve as diagnostic biomarkers and are emerging as novel therapeutic targets for CNS injuries. MiRNA-based therapeutics include miRNA mimics and inhibitors (antagomiRs) to respectively decrease and increase the expression of target genes. In this review, we summarize current miRNA-based therapeutic applications in stroke, TBI and SCI. Administration methods, time windows and dosage for effective delivery of miRNA-based drugs into CNS are discussed. The underlying mechanisms of miRNA-based therapeutics are reviewed including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis and neurogenesis. Pharmacological agents that protect against CNS injuries by targeting specific miRNAs are presented along with the challenges and therapeutic potential of miRNA-based therapies.

Keywords: MicroRNA mimics; microRNA inhibitors; spinal cord injury; stroke; traumatic brain injury.

Figure 1.

Altered miRNAs regulate target genes resulting in multiple outcomes after CNS injuries. Dysfunctioned miRNAs during CNS injuries causes multiple pathological outcomes, including neuronal death, neurogenesis and angiogenesis impairments, platelets aggregation, leucocytes infiltration, BBB disruption, tissue infarction, neurological deficits, and others. Left panel: Increased miRNAs lead to down-regulation of their target genes, resulting in deteriorated outcomes after CNS injuries. The miRNA-target gene pairs include miR-497::Bcl-2, Let-7f::IGF-1, miR-181::SHPA5, miR-15a/16::FGFR1/VEGFR2/FGF2, and others. Right panel: Decreased miRNAs lead to up-regulation of their target genes, resulting in detrimental outcomes after CNS injuries. The miRNA-target gene pairs include miR-124::ROCK/Src, miR-122::Pla2g2a/Rhbdf1/NOS2, miR-21::PTEN, and others. MiRNA inhibitors or mimics can either suppress increased miRNAs or elevate decreased miRNAs, respectively, to improve multiple outcomes after CNS injuries.

Figure 2.

Function of circulating microRNAs in CNS injuries. During CNS injuries, decreased miRNAs in blood lead to upregulation of their target inflammatory genes and blood clotting genes, and thus results in multiple outcomes after CNS injuries, including leukocyte-platelet-endothelium complexes, platelet aggregation, leukocyte infiltration, BBB disruption, tissue infarction, neurological deficits, and others. MiRNA mimics replace the decreased miRNAs in blood and accordingly attenuate these detrimental outcomes after CNS injuries.

Figure 3.

MicroRNA-based therapeutics in experimental diseased animal models and human patients. (a) MiRNA-based therapeutic applications in animal models of human diseases. In animal models, various miRNA-based therapeutics possess promising treatment potential against different human diseases, including cardiovascular diseases, obesity-associated disorders, atherosclerosis, cancers, liver diseases, neurodegenerative diseases and central nervous system (CNS) injuries. (b) MiRNA-based therapeutic applications in patients. To our knowledge, five miRNA-based drugs have been tested in clinical trials. Miravirsen and RG-101 are miR-122 inhibitors and are designed for the treatment of HCV-induced liver disease. RG-125/AZD4076 is miR-103/107 inhibitor and is designed for the treatment of Type 2 Diabetes and non-alcoholic fatty liver diseases. MRX34 is miR-34 mimic and is designed for the treatment of advanced hepatocellular carcinoma. TargomiRs is miR-16 mimic and is designed for the treatment of recurrent thoracic cancer. “↑”, upregulate miRNA levels by various miRNA mimics; “↓”, downregulate miRNA levels by various miRNA inhibitors.

Figure 4.

MicroRNA-based therapeutics for CNS injuries in experimental animal models. In the brain or spinal cord, downregulating miRNA expression by specific miRNA inhibitors, or upregulating miRNA expression by specific miRNA mimics in experimental animal models of stroke, traumatic brain injury (TBI) or spinal cord injury (SCI) revealed potential therapeutic effects against these CNS injuries. Currently, the delivery methods for the miRNA mimics or inhibitors mainly include intracerebroventricular (ICV) injection, continuous ICV infusion with osmotic minipumps, intravenous (IV) administration, intranasal administration, intrathecal administration, virus-mediated delivery, exosome-mediated delivery and stem cell-mediated delivery. In addition, a number of miRNA-based drugs have been administrated to experimental animals by combined methods to achieve the maximal delivery efficacy.

Figure 5.

Mechanisms of microRNA-based therapeutics for CNS injuries. Therapeutic mechanisms of microRNA-based drugs for stroke (A), traumatic brain injury (TBI, B) and spinal cord injury (SCI, C). (a) Upregulation or downregulation specific miRNAs in the brain exhibits protective effects against stroke via different mechanisms, including anti-excitotoxicity, anti-oxidative stress, anti-inflammation, anti-apoptosis, BBB protection and edema reduction, pro-angiogenesis, pro-neurogenesis, anti-neurodegeneration, maintain ionic homeostasis and activation of autophagy. (b) Manipulation of several miRNAs exerts neuroprotection again TBI through mechanisms involving anti-inflammation, anti-apoptosis, BBB protection, pro-angiogenesis, pro-neurogenesis and anti-neurodegeneration. (c) A number of miRNAs are also involved for the potential therapy of SCI through various mechanisms, including anti-oxidative stress, anti-inflammation, anti-apoptosis, anti-neurodegeneration, BSCB protection and edema reduction, pro-angiogenesis and pro-neurogenesis. Moreover, many miRNAs possess the ability to regulate the pathophysiological events against CNS injuries via several different mechanisms. “↑”, upregulate miRNA levels by miRNA mimics; “↓”, downregulate miRNA levels by miRNA inhibitors.