Development of therapies for rare and intractable genetic diseases by delivery of nucleic acid editing tools

Integrating diagnosis and treatment: Personalized medicine to directly correct mutations via "nucleic acid editing"

In recent years, advances in genome analysis technology have made it possible to identify the genetic mutations responsible for many hereditary diseases. However, even when a diagnosis is possible, many diseases remain for which no effective treatment exists. For severe genetic diseases that manifest during the neonatal or infantile period, the time from diagnosis to treatment is limited, and it is important to have a system that leads to treatment as early as possible. Furthermore, because the number of patients with rare diseases is small, it is difficult for companies alone to advance drug development due to cost constraints.

For this reason, it is necessary to establish a new system of collaboration that includes academia and venture companies. Our research group aims to build a "nucleic acid editing medical pipeline" that integrates everything from genomic diagnosis to the development and provision of therapeutic materials. The objective is to establish a social implementation model for personalized medicine that precisely corrects DNA or RNA according to each patient's specific genetic mutation, directly linking diagnostic results to treatment design. Specifically, an important objective of our research is to establish a system that mainly addresses DNA correction via genome editing or RNA modification via antisense oligonucleotides (ASO) to enable selection of the optimal treatment strategy based on the type of disease and the nature of the mutation.

While many conventional gene therapies have relied on supplementing normal genes (cDNA), they have faced challenges such as the difficulty of controlling expression and the risk of carcinogenesis caused by the integration of viral vector-derived DNA into the genome.

Our research emphasizes "correcting or controlling the mutation itself," utilizing nucleic acid editing technology that intervenes directly at the cause of the disease. In particular, we aim to achieve high-safety and high-precision treatment design using original technology that utilizes DNA repair mechanisms triggered by single-strand breaks, without requiring double-strand breaks or foreign DNA.

Another pillar of our work is the development of delivery technology to transport editing tools directly to target organs in vivo. We are focusing on hematopoietic diseases where corrected gene cells are likely to gain a proliferative advantage within the body, creating a situation where therapeutic effects can be expected even from a small number of corrected cells.

We are also conducting verifications for muscular diseases. By improving and integrating delivery technologies using mRNA, ribonucleoproteins, and lipid nanoparticles, we aim to realize in vivo genome editing therapies that do not require ex vivo manipulation.

Currently, we are verifying therapeutic effects using model animals and patient-derived cells, primarily focusing on immunodeficiencies and muscular dystrophies. For certain diseases, ASO therapy acting at the RNA level is also a clinical candidate. Additionally, for safety evaluation, we are performing comprehensive analyses of off-target mutations based on whole-genome sequencing and accumulating empirical data.

In this research, we are strategically selecting target diseases, genome editing methods, and delivery techniques with significant growth potential, advancing research and development with an eye toward transitioning to the clinical stage. Through this stepwise refinement, we will connect research results to actual medical practice.

Because the number of patients is small, the development of treatments for many genetic diseases has often been deprioritized. However, with the progress of nucleic acid editing technology, treatments that act directly on the causative genes are becoming a realistic option.

This research demonstrates a new medical flow that integrates diagnosis and treatment, building a mechanism to deliver therapies to patients in need more quickly. Through these efforts, we intend to change the nature of medical care for rare diseases and lead the way to a future where the optimal treatment can be provided to every individual patient.