Enhancing miRNA Therapeutic Efficacy Through Combinatorial Targeting and Vehicle Free Delivery
Abstract
New alternative therapies to treat cancer have emerged such as the use of small molecules that target key oncogenic drivers. For instance, clinically relevant tumor suppressive microRNAs (miRNAs) that target key oncogenic drivers have been identified as potential therapeutics to treat cancer. MiRNAs are small non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. It has been shown that aberrant miRNA expression, through misexpression of miRNA target genes, can have profound cellular effects leading to a variety of diseases, including cancer. While altered miRNA expression contributes to a cancerous state, restoration of miRNA expression has therapeutic benefits. For example, ectopic expression of miRNA-34a (mir-34a), a tumor suppressor miRNA that is a direct transcriptional target of p53 and thus is reduced in p53 mutant tumors, has clear effects on cell proliferation and survival in murine models of cancer. It is expected that miRNA replacement therapies will have profound effects in the clinic; however, miRNA therapeutics are still in their infancy and there are critical challenges that need to be addressed for the advancement of miRNA-based therapies. Firstly, one of the biggest challenges for miRNA advancement into the clinic is efficient delivery of miRNA mimics due to problems such as delivery-associated toxicity, poor transfection, systemic clearance, poorly understood biodistribution, degradation in circulation, immune response, and endosomal sequestration. Secondly, strategies to enhance the therapeutic efficacy of a miRNAs, such as through combinatorial miRNA therapeutics, have yet to be explored meticulously. Therefore, there is a critical need to identify strategies to overcome these obstacles and facilitate the advancement of miRNA therapies into clinical trials. For that reason, we hypothesized that a ligand targeted miRNA strategy could be used for successful delivery of therapeutic miRNAs into target tissues. Furthermore, since miRNAs can regulate multiple gene targets we also hypothesized that two or more miRNAs could potentially collaborate to repress the expression of numerous cancer- related genes in various pathways. The results presented here show i) that unprotected functional miRNA mimics can be delivered to solid tumors using vehicle free ligand- mediated delivery, ii) that the implementation of endosomal escape mechanism helps to increase targeting efficacy leading to a reduction in the effective dose and iii) that miRNA combinations have enhanced efficacy for lung cancer. Collectively these studies will address an unmet need of identifying, characterizing, and therapeutically targeting miRNAs for the treatment of cancer.
Degree
Ph.D.
Advisors
Kasinski, Purdue University.
Subject Area
Cellular biology|Molecular biology|Genetics
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