MicroRNA-Regulated Gene Delivery Systems for Research and Therapeutic Purposes

Abstract

Targeted gene delivery relies on the ability to limit the expression of a transgene within a defined cell/tissue population. MicroRNAs represent a class of highly powerful and effective regulators of gene expression that act by binding to a specific sequence present in the corresponding messenger RNA. Involved in almost every aspect of cellular function, many miRNAs have been discovered with expression patterns specific to developmental stage, lineage, cell-type, or disease stage. Exploiting the binding sites of these miRNAs allows for construction of targeted gene delivery platforms with a diverse range of applications. Here, we summarize studies that have utilized miRNA-regulated systems to achieve targeted gene delivery for both research and therapeutic purposes. Additionally, we identify criteria that are important for the effectiveness of a particular miRNA for such applications and we also discuss factors that have to be taken into consideration when designing miRNA-regulated expression cassettes.

The Therapeutic Potential of MicroRNAs as Orthobiologics for Skeletal Fractures

“…Clearly, utilizing already characterized miRNAs is a valid starting point and again, Scimeca and Verron classify miRNAs in various functional categories, including bone homeostasis (bone formation and resorption) and bone pathologies (osteoporosis, fractures, cancer, and even osteogenesis and angiogenesis). As such, we are beginning to amass functional categories of characterized miRNAs that should serve as a good starting point for selection …”

“…As such, we are beginning to amass functional categories of characterized miRNAs that should serve as a good starting point for selection. (77) Designing therapeutic miRNA replacement or inhibition approaches is not trivial and one of the biggest obstacles is off-target effects because individual miRNAs are pleiotropic in nature. Obviously, off-target effects can lead to adverse effects in other tissues and organs, especially if the therapeutic application is systemic, even though this approach also has hurdles from miRNA mimic or inhibitor degradation by abundant nucleases present in the plasma and extracellular environment, as well as removal from the circulation by the liver and kidneys.…”

Advances in Orthodontic Tooth Movement: Gene Therapy and Molecular Biology Aspect

“…The degree of perfect complementarity at nucleotides 2-8 (binding sequence) in the 5 0end of the miRNA is essential for a successful action of the RISC complex. Depending on the extent of complementarity with the target sequence, gene expression is repressed either by inhibition of translation or by cleavage of the corresponding mRNA [114]. The process of gene therapy using endogenous miRNAs involves selection process of miRNA candidates, design of expression cassettes if constant expression is needed, selection of delivery carrier, and evaluation of system in cells, animal models and clinical trials [114].…”

“…Depending on the extent of complementarity with the target sequence, gene expression is repressed either by inhibition of translation or by cleavage of the corresponding mRNA [114]. The process of gene therapy using endogenous miRNAs involves selection process of miRNA candidates, design of expression cassettes if constant expression is needed, selection of delivery carrier, and evaluation of system in cells, animal models and clinical trials [114]. Several miRNAs have been reported for their expression and roles in PDL and alveolar bones [115][116][117][118].…”

MicroRNA199a-Based Post-transcriptional Detargeting of Gene Vectors for Hepatocellular Carcinoma

“… 12 , 13 , 14 In this negative targeting method, binding sites of miRNA expressed at high levels in target cells are incorporated at the UTRs of transgene, and, as a result, transgene expression gets inhibited in those cells ( Figure 2 A). 15 …”