Development of a novel treatment for the predominant Japanese mutation in glycogen storage disease Type Ia using novel high-performance splice-switching oligonucleotides

A path to curative treatment for rare genetic diseases: Correcting aberrant splicing with high-performance nucleic acids

In recent years, splice-switching oligonucleotides (SSOs)-nucleic acid drugs that regulate gene expression-have been brought to clinical use and are demonstrating groundbreaking therapeutic effects for diseases that were previously difficult to treat. Through our research, we have developed novel high-performance SSOs that enable potent and sustained splicing control in the liver by combining a highly efficient hepatocyte delivery technology (GalNAc modification) with a chemically modified nucleic acid technology (ENA) that offers high binding affinity for complementary RNA and excellent in vivo stability. Under the Research and Development Program for Innovative Biologics, we are applying this technology to the predominant Japanese mutation in glycogen storage disease type Ia (GSDIa).

GSDIa is an inborn error of metabolism caused by loss-of-function mutations in the G6PC gene, which encodes glucose-6-phosphatase (G6Pase), the enzyme that converts glycogen to glucose in the liver. The disease is characterized by hepatomegaly due to glycogen accumulation in the liver and hypoglycemia caused by decreased blood glucose levels. Hepatomegaly appears in early childhood and may progress to liver cancer in the future, making early and appropriate management important, yet no effective treatment currently exists. Hypoglycemia is particularly prone to becoming severe in infancy and early childhood and carries the risk of causing central nervous system damage. A strict dietary regimen centered on frequent intake of high-carbohydrate foods is the standard of care. However, this treatment places a heavy physical and psychological burden on patients and their families, and it is difficult to completely prevent hypoglycemic episodes, even with strict management. Moreover, many of the secondary metabolic disorders and hepatic lesions caused by hypoglycemia remain inadequately controlled, and there is a strong demand for the development of a curative treatment.

GSDIa follows an autosomal recessive inheritance pattern and, with a prevalence of approximately 1 in 100,000 people in Japan, is classified as a rare metabolic disease and designated as an intractable disease. The disease has race-specific predominant mutations; in East Asia, the G6PC gene c.648G>T variant is the most prevalent (allele frequency in affected individuals: 91% in Japanese, 75% in Koreans, and 54% in Chinese). This variant causes aberrant splicing and leads to the loss of G6Pase activity. We are working on this program with the belief that correcting this splicing abnormality using our novel high-performance SSOs can make a curative treatment for GSDIa a reality.

In our research to date using a proprietary GSDIa model mouse (c.648G>T knock-in mouse), we have identified a promising SSO that shows marked therapeutic efficacy and raises no serious safety concerns in up to three months of administration (Ito K, et al., J Clin Invest., 2023). Under this program, we aim to develop this SSO as a breakthrough new drug for GSDIa by completing the preclinical studies required for a Phase I/II repeat-dose clinical trial in pediatric patients and advancing to the clinical trial stage. The preclinical studies required for a Phase I/II single-dose trial in adult patients have already been completed. We will now proceed with investigational drug manufacturing, juvenile mouse studies, reproductive toxicity studies, long-term toxicity studies, and the drafting of the clinical trial protocol. Through this program, we aim to verify the clinical efficacy and safety of this technology and, by out-licensing to industry, pursue the commercialization of an innovative therapeutic for GSDIa, a disease for which no curative treatment currently exists.