Research and development of systemically administered antitumor nucleic acid drug MIRX006 based on microRNA

Toward cancer treatment that "allows no resistance:" Leveraging pH-responsive LNPs

In current cancer treatment, molecular targeted drugs that use small-molecule compounds and antibody drugs have become the mainstream of therapy because they show high affinity for specific target factors. However, most of these conventional approaches target a "single gene (or protein)." There are cases in which sufficient therapeutic effects are not achieved in cancers characterized by disruption of multiple signaling pathways and heterogeneous cell populations.

Conventional cancer treatment also faces two major barriers. The first is that many genes are deeply involved in cancer malignancy and metastasis yet are difficult to control with existing molecular targeted drugs due to structural issues in the target protein—so-called "undruggable targets." The second is that compensatory signal activation triggered by single-molecule inhibition leads to the acquisition of "drug resistance," which significantly worsens prognosis. There is an urgent need to create new treatment modalities capable of overcoming these challenges.

We have focused on nucleic acid drugs as a next-generation anticancer agent to overcome this situation—in particular, we have looked at "microRNA (miRNA)," a type of non-coding RNA. miRNA has a "multi-molecular targeting capability" not found in existing drugs: a single molecule can broadly suppress the expression of multiple target messenger RNAs (mRNAs) that carry complementary sequences.

Our research group has independently discovered that a specific miRNA, "miR-3140-3p," exhibits extremely potent antitumor effects. In diseases such as cancer, where multiple genetic abnormalities and the breakdown of complex signaling control occur simultaneously, miR-3140-3p, which can comprehensively target multiple pathways, has strong potential as a drug discovery seed. In this research, we have adopted miR-3140-3p as the main component of a nucleic acid drug, aiming to achieve "cancer treatment that allows no resistance," something that has been beyond the reach of conventional molecular targeted drugs.

The greatest barriers to the practical application of nucleic acid drugs are the efficiency of delivery to target tissues, stability in the body, and avoidance of side effects on normal tissues. In this research, we are simultaneously developing a highly tumor-selective delivery system to maximize the potential of miR-3140-3p.

More specifically, we are making use of a physiological characteristic: the fact that the microenvironment surrounding solid tumors is more "acidic (low pH)" than normal tissue. In this research, we designed lipid nanoparticles (LNPs) using "pH-responsive lipids" that are taken up into cells only under specific acidic conditions. This enables us to build a system that remains stable in the bloodstream yet efficiently releases and delivers miRNA into cells in response to the acidic environment upon reaching the tumor tissue. Through this technology, we aim to achieve highly effective drug delivery with minimal side effects even with systemic administration.

In this research, we are integrating "miR-3140-3p," which has potent antitumor activity, with this "tumor-selective delivery technology," and are advancing the development of MIRX006 as a novel, systemically administered nucleic acid drug candidate. Development is being carried out along two parallel lines. The first is biological evaluation, aimed at verifying efficacy across cancer types, elucidating the detailed mechanism of action, and accumulating non-clinical data through safety testing. The second is physical research and manufacturing development, aimed at optimizing the lipid nanoparticles and establishing a production method with pharmaceutical development in mind.

By carrying out in-depth research along these two lines, we aim to ensure the "clinical stage advancement (entry into clinical trials)" of MIRX006. Completion of this research will not only provide new treatment options for patients with refractory cancer but will also make a significant contribution to the establishment of a nucleic acid drug platform in Japan.