microRNA Therapeutic Programs
Asuragen’s microRNA (miRNA) therapeutics program is directed toward identifying and validating miRNAs that contribute to the development of cancer and other diseases. Once identified, these miRNAs are being evaluated as potential therapeutics or therapeutic targets using cell and animal models of the target disease. We are identifying miRNAs that are involved in a variety of diseases by using a combination of miRNA expression analysis and miRNA functional analysis. For expression analysis, we evaluate samples from patients to identify those miRNAs that are most consistently and significantly expressed at different levels between a disease tissue and a normal tissue. For the miRNA function studies, we use cell models for the disease to evaluate the effect of introducing mimetics or inhibitors for each of the miRNAs into the cells. Those miRNAs that affect phenotypes associated with the disease are considered to be potential therapeutic intervention points. We then compare the expression and function data to identify those miRNAs that have expression levels that are consistently altered in disease samples and that also affect phenotypes associated with the disease. Identifying the genes that are regulated by the candidate miRNAs is then used to understand the relationship between the miRNAs and the disease.
| miRNA Expression Analysis: | miRNA Functional Analysis | ||
Compare miRNA profiles of disease and normal samples |
Introduce or inhibit all known miRNAs in cell samples and monitor phenotypes |
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miRNAs that contribute to human disease |
Depending on whether a miRNA must be up- or down-regulated in order to contribute to the development of a disease, the ideal therapeutic would either be an inhibitor (a molecule that disrupts the function of the miRNA) or a mimetic (a molecule that functions like the miRNA). We have developed technologies for both. Our inhibitors are antisense molecules that bind and inactivate miRNAs of a specific sequence. Multiple labs are using equivalent technology to evaluate their therapeutic potential. We have validated the concept of “miRNA Replacement Therapy” which involves introducing synthetic miRNAs into diseased tissues in an effort to restore normal proliferation, apoptosis, cell cycle, and other pathways that have been affected by down-regulation of one or more miRNAs. In many cases, reactivation of these miRNA-regulated pathways leads to a therapeutic response.
Based on critical clinical needs and the mounting evidence that miRNAs play a causative role in the development of cancer, much of Asuragen’s efforts have been directed toward identifying miRNAs that are involved in the development of multiple cancers. Toward that end, we have identified miRNAs whose expression levels are significantly altered in tumors and whose functions in cells relate to critical proliferative processes like cell cycle, apoptosis, telomere maintenance, and viability. We have found that some miRNAs have attributes that are consistent with well known oncogenes while others appear to function as tumor suppressors. Oncogenes are defined as genes whose over-expression or inappropriate activation leads to oncogenesis. Tumor suppressors are genes that are required to keep cells from being cancerous; the down-regulation or inactivation of tumor suppressors is a common inducer of cancer. The finding that some miRNAs function as oncogenes while others act as tumor suppressors is important given the emphasis that others in the pharmaceutical industry have placed on targeting oncogenes and tumor suppressors. Interestingly, many of the miRNAs that act like tumor suppressors or oncogenes regulate the expression of known protein-coding oncogenes and tumor suppressors, providing a likely relationship between the altered expression of one or a few miRNAs and the development of cancer.
Asuragen miRNA Therapy Programs
Based upon the critical involvement of miRNAs in the disease path, the availability of a delivery system for the disease cells or tissues, and clinical need, we are focusing on the following diseases for our miRNA-based therapeutics program:
Lung Cancer [Learn more]
We have used miRNA expression analyses in lung tumors and miRNA functional studies in lung cancer cell lines to identify miRNAs with therapeutic potential. The focus of our studies are miRNAs that consistently show lost or reduced expression levels in lung cancer samples and – when introduced into lung cancer cells – affect cell proliferation, viability, apoptosis, and/or cell cycle. These miRNAs are being tested in animal models for their capacity to reduce or eliminate tumor growth either when used alone or in combination with chemo- or radiation therapy.
Leukemia [Learn more] Asuragen has profiled the expression of miRNAs in white blood cell populations from leukemia patients and identified a set of miRNAs that show consistently altered expression levels in leukemic cells. Introduction of some of these miRNAs reduces cell growth and viability of multiple leukemia cell lines. Animal studies are being initiated to verify that leukemia cells respond to the introduction of specific miRNAs in vivo.
Prostate Cancer [Learn more]
Asuragen’s expression studies and functional studies have identified several miRNAs whose altered expression in prostate cells appears to contribute to their malignancy. These miRNAs are being evaluated as therapeutic agents in mouse models.
Macular Degeneration [Learn more]
We have identified several miRNAs whose expression levels are altered in patient samples as well as animal models of the disease. Animal experiments are planned to evaluate the therapeutic efficacy of introducing single and combinations of synthetic miRNAs into the eyes of animal models.