Development of novel therapy due to correcting splicing error of patients with galactosialidosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17298
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kobe University
• Principal Investigator: Bo Ryosuke 神戸大学, 医学部附属病院, 助教 (10749188)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ガラクトシアリドーシス / CTSA遺伝子 / ライソソーム病

Outline of Final Research Achievements

Galactosialiodosis is a rare lysosomal disease, caused by mutation in the CTSA gene. In Japanese cases, common variant, IVS7＋3A>G, has been identified, which was related to the milder phenotype. However, this mechanism of genotype and phenotype was not fully declared. At first, we analyzed the splicing pattern of this variant both in vivo and vitro. In previous report, this common variant produced exon 7 skipping and normal mRNA. However, our study revealed normal mRNA was not obtained in both. Furthermore, novel alternative splicing product including gt insertion was demonstrated. Skipping of exon 7 (92 bases) was assumed to cause nonsense medicated decay, but this product could be strongly related to the milder phenotype. We planed to clarify whether the specific antisense nucleotide can modify the splicing pattern of CTSA gene or not, but we can not obtain any sufficient effect However, this new splicing variant could be the novel target of therapy with galactosialidosis.

Free Research Field

先天代謝異常症

Academic Significance and Societal Importance of the Research Achievements

本研究では、日本人ガラクトシアリドーシス患者に多くみられる遺伝子変異に関して検討をおこなった。従来本変異による軽症化の機序は、通常のｍRNA産物が一部で産生されるためと考えられていた。しかし本研究から、本変異からの正常mRNAは確認できず、exon7が欠失したうえで2塩基の挿入がみられる新規のスプライシング産物が認められた。これは従来想定されていたものとは異なる機序で臨床像に影響を与えている可能性を示唆している。本研究ではスプライシングを修正し正常化させる薬剤の同定まではできなかったが、新規の治療対象となりうる軽症化のメカニズムに関しての新たな知見が得られた。