Development of therapeutic applications for intractable neurological and muscular diseases based on innovative nucleic acid drug technology

From Japan's "bridged artificial nucleic acid" to the "clinic" — Aiming for fundamental treatment of intractable neurological and muscular diseases

The development of innovative biopharmaceuticals originating from Japan is an urgent challenge in the fields of medicine and drug discovery. There are great expectations for the research and development of nucleic acid drugs for intractable diseases. Nucleic acid drugs are attracting attention as a new drug discovery modality that can directly control genes that have been difficult to target with conventional small-molecule drugs or antibody drugs. However, challenges such as reducing side effects and achieving efficient delivery to target organs remain unresolved.

Over many years, we have advanced research grounded in nucleic acid chemistry and were the first in the world to successfully create bridged artificial nucleic acids. In addition to developing artificial nucleic acids to improve the efficacy of nucleic acid drugs and establishing chemical modification technologies to enhance safety, in recent years we have also worked on delivery technologies that enable delivery to target tissues such as the brain and muscles. These achievements have helped overcome several challenges facing nucleic acid drugs. The efficacy and safety of nucleic acid drugs incorporating artificial nucleic acids have been demonstrated through a series of nonclinical studies.

This research project is performed under an open innovation framework involving the University of Osaka's Graduate School of Pharmaceutical Sciences and Graduate School of Medicine, Kyoto University's Graduate School of Medicine, and venture companies specializing in nucleic acid drug discovery. The research and development of nucleic acid drugs is advanced in this project for intractable diseases including multiple system atrophy, Parkinson's disease, and muscular dystrophy. Symptomatic therapy is currently the primary treatment option for multiple system atrophy and Parkinson's disease, and there is a strong need to develop disease-modifying drugs that can suppress disease progression. In the case of muscular dystrophy, although nucleic acid drugs that induce exon skipping have recently emerged, a challenge remains in that applicable patients are limited to those with specific genetic mutations.

To address these challenges, this research designates nucleic acid drugs targeting multiple system atrophy and Parkinson's disease as "Seed A," and those targeting muscular dystrophy as "Seed B," with development proceeding based on distinct mechanisms of action for each. For Seed A, antisense nucleic acids designed to induce the degradation of disease-causing target mRNA have been designed and synthesized, with careful consideration given to delivery to the central nervous system and safety upon administration. For Seed B, the focus is on anti-miRNA nucleic acids that inhibit the function of miRNAs involved in muscle pathology, with the aim of establishing a treatment concept expected to be applicable to a broad patient population.

The nucleic acid drug candidates obtained for Seed A and Seed B have been evaluated using cell and animal models, and sequence design and chemical structure optimization have been advanced with the goal of achieving both efficacy and safety. As a result, promising candidate compounds with high therapeutic potential have been successfully identified for both seeds. Currently, work is underway to establish synthesis methods scalable to manufacturing, develop analytical methods to ensure quality, and begin preliminary safety studies, with an eye toward future clinical application and commercialization.

Going forward, nonclinical safety studies, pharmacokinetic studies, and off-target profiling will be systematically conducted and a data package meeting regulatory requirements will be built under the framework of the AMED Research and Development Program for Innovative Biologics, with the goal of advancing both Seed A and Seed B "to the clinical stage." The ultimate goal is to translate these research outcomes into practical applications through industry-academia collaboration and partnerships with companies, and to deliver these nucleic acid drugs originating from Japan to patients suffering from these diseases.