JP-2026514437-A - Compositions and methods for the treatment or prevention of TAR DNA-binding protein 43-related diseases

Abstract

A composition for use in the treatment or prevention of TAR DNA-binding protein 43-related diseases, comprising a substance that promotes the increase of intracellular amounts of proteins having ubiquitination activity.

Inventors

• 田村 誠
• 白川 峰征
• 村谷（御厨） 颯季

Assignees

• 田辺ファーマ株式会社

Dates

Publication Date

20260511

Application Date

20240328

Priority Date

20230331

Claims (16)

1. A composition for the treatment or prevention of TAR DNA-binding protein 43-related diseases, comprising a substance that promotes the increase of intracellular amounts of proteins with ubiquitination activity.
2. A composition for improving the clearance of TAR DNA-binding protein 43, containing a substance that increases the intracellular amount of proteins with ubiquitination activity.
3. The composition according to claim 1 or 2, for use in subjects who have developed or are at risk of developing TAR DNA-binding protein 43-related disease.
4. The composition according to claim 3, wherein the TAR DNA-binding protein 43-related disease is amyotrophic lateral sclerosis, frontotemporal lobar degeneration, or limbic-dominant senile TDP-43 encephalopathy.
5. The composition according to claim 1 or 2, wherein the promoting substance is a protein having ubiquitination activity that increases the intracellular amount of LRSAM1 protein.
6. The composition according to claim 5, wherein the protein is the wild-type LRSAM1 protein.
7. The composition according to claim 1 or 2, wherein the promoting substance is a substance that promotes the production of a translation product from a nucleic acid encoding the LRSAM1 protein, thereby increasing the intracellular amount of the LRSAM1 protein.
8. The composition according to claim 7, wherein the protein is the wild-type LRSAM1 protein.
9. The composition according to claim 1 or 2, wherein the promoting substance is a substance containing nucleic acid.
10. The composition according to claim 9, comprising one or more selected from expression-enhancing nucleic acids and expression vectors as the promoting substance.
11. The composition according to claim 1 or 2, wherein the cells are nerve cells.
12. The process includes administering an effective amount of a promoting agent to a subject requiring it, A method for treating or preventing TAR DNA-binding protein 43-related disease, wherein the promoting substance is a substance that increases the intracellular amount of a protein having ubiquitination activity.
13. The method according to claim 12, wherein the disease is treated or prevented by administering the promoting substance to the subject to suppress the occurrence or progression of nerve cell damage.
14. Use of a promoter that increases the intracellular amount of ubiquitinating proteins in the manufacture of a composition for treating or preventing TAR DNA-binding protein 43-related diseases.
15. A method for suppressing cell damage, comprising bringing a substance that increases the intracellular amount of ubiquitinating proteins into contact with a neuron, thereby suppressing the occurrence or progression of neuronal cell damage.
16. A method for improving protein clearance, comprising bringing a neuron into contact with a substance that increases the intracellular amount of a protein having ubiquitination activity, thereby improving the clearance of TAR DNA-binding protein 43 in the neuron.

Description

This application, referenced to related applications, claims priority based on U.S. Application No. 63/493,462 dated March 31, 2023, and U.S. Application No. 63/597,559 dated November 9, 2023. The full texts of these applications are incorporated herein by reference. Reference to the Sequence Listing This specification refers to the sequence listing submitted electronically as an .xml file named "541677WO_ST26.xml" in accordance with WIPO standard ST.26. The .xml file was created on March 26, 2024, and its size is 49,152 bytes. The full text of the sequence listing is incorporated herein by reference. This disclosure relates to compositions and methods for treating or preventing TAR DNA-binding protein 43-related diseases. Patent Document 1 discloses a compound that improves messenger RNA (mRNA) splicing. The same document also discloses a treatment method for familial autonomic neuropathy, a progressive neurodegenerative disease, as an example. Non-patent document 1 focuses on Charcot-Marie-Tooth disease type 2P and describes suppressing cell death associated with the accumulation of misfolded proteins. This document discloses that LRSAM1 suppresses the accumulation of misfolded luciferase and reduces cytotoxicity. Patent Document 1: US 2018/0118748 A1 Non-patent document 1: Mishra R et al., Int J Biochem Cell Biol. 2020; 120:105697 The entire contents of these publications are incorporated herein by reference. One embodiment of the present disclosure is a composition for use in the treatment or prevention of TAR DNA-binding protein 43-related diseases, comprising a promoter that increases the intracellular amount of a protein having ubiquitination activity. Another embodiment of the present disclosure is a composition for improving the clearance of TAR DNA-binding protein 43, comprising a promoter that increases the intracellular amount of a protein having ubiquitination activity. Furthermore, one embodiment of the present disclosure includes the step of administering an effective amount of the promoting substance to a subject requiring it, A method for treating or preventing TAR DNA-binding protein 43-related disease, wherein the promoting substance is a substance that increases the intracellular amount of a protein having ubiquitination activity. Another embodiment of this disclosure involves the use of a promoter that increases the intracellular amount of a ubiquitinating protein in the preparation of a composition for treating or preventing TAR DNA-binding protein 43-related diseases. Another embodiment of the present disclosure is a method for suppressing cell damage, which involves bringing a neuron into contact with a substance that increases the intracellular amount of a protein having ubiquitination activity, thereby suppressing the occurrence or progression of cell damage in the neuron. Another embodiment of the present disclosure is a method for improving protein clearance, which involves bringing a neuron into contact with a substance that increases the intracellular amount of a protein having ubiquitination activity, thereby improving the clearance of the TAR DNA-binding protein 43 protein in the neuron. To fully understand the present invention and its many advantages, please refer to the following detailed description in conjunction with the accompanying drawings. Figure 1 is a graph showing the degree of cellular damage in motor neurons derived from healthy individuals and motor neurons derived from ALS patients, using neurite length as an indicator.Figure 2 is a graph showing the cytoplasmic/nuclear abundance ratio of TDP-43 protein in motor neurons derived from healthy individuals and motor neurons derived from ALS patients.Figure 3 is a graph showing the amount of phosphorylated TDP-43 protein present in the cytoplasm of motor neurons derived from healthy individuals and motor neurons derived from ALS patients.Figure 4 is a graph showing the effect of the presence or absence of stimulating substances on neurite length in motor neurons derived from healthy individuals.Figure 5 is a graph showing the effect of the presence or absence of stimulating substances on neurite length in motor neurons derived from ALS patients.Figure 6A is a graph showing the cytoplasmic/nuclear abundance ratio of TDP-43 protein in motor neurons derived from healthy individuals, depending on the presence or absence of a stimulating substance.Figure 6B is a graph showing the cytoplasmic/nuclear abundance ratio of TDP-43 protein in motor neurons derived from ALS patients, with and without the presence of a stimulating substance.Figure 7A is a graph showing the amount of phosphorylated TDP-43 protein present in the cytoplasm of motor neurons derived from healthy individuals.Figure 7B is a graph showing the amount of phosphorylated TDP-43 protein present in the cytoplasm of motor neurons derived from ALS patients.Figure 8 is a graph showing the effect of the ratio of mRNA containing cryptic exons (CE) to full-length