Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease.

Overview

Authors: Miguel da Silva Padilha^1,2,3, Seda Koyuncu^3,4, Evangeline Chabanis¹, Sergey Ryazanov⁵, Andrei Leonov⁵, David Vilchez^3,4,6, Rüdiger Klein², Armin Giese⁷, Christian Griesinger^5,8, Irina Dudanova^1,2,3,9

ORCID iDs: Miguel da Silva Padilha, Andrei Leonov, David Vilchez, Rüdiger Klein, Christian Griesinger, Irina Dudanova

Center for Anatomy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Department of Molecules – Signaling – Development, Max Planck Institute for Biological Intelligence, Martinsried, Germany
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany
Department of NMR Based Structural Biology, Max Planck Institute of Multidisciplinary Sciences, Göttingen, Germany
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
MODAG GmbH, Wendelsheim, Germany
Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany
Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany

Institutions: University of Cologne (Germany); Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (Germany); University Hospital Cologne (Germany); Max Planck Institute for Biological Intelligence; Max Planck Institute for Multidisciplinary Sciences (Germany); Multiscale Bioimaging; University of Göttingen (Germany); University of Würzburg (Germany)

Journal: EMBO molecular medicine, volume 18, issue 7, pages 2838-2866

Dates: received 5 March 2025; accepted 20 May 2026; published online 26 June 2026; in print July 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s44321-026-00459-9 · PMID 42362792 · PMCID PMC13365221 · OpenAlex W4408393464

Open access: gold, a free copy (OpenAlex)

Preprint: doi:10.1101/2025.03.11.642540

Status: data only

Categories: human (organism), mouse (organism), other condition (population), cellular / molecular (subfield)

Methods: fMRI & imaging

Keywords: Neuroscience

MeSH: Huntington Disease*, Animals, Brain, Cells, Cultured, Disease Models, Animal, Humans, Huntingtin Protein, Mice, Nerve Tissue Proteins, Neurons, Phenotype (* major topic)

Topic: Genetic Neurodegenerative Diseases (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex

Funding: Deutsche Forschungsgemeinschaft (DFG) (EXC 2067/1-390729940, SPP2453 project number 541742535, EXC 2030-390661388, FOR5762 project number 531902955, SFB1451 project number 431549029)

Citations: not cited yet (Europe PMC); 77 references in the paper

Research resources: RRID:AB_2313584, RRID:AB_2340375, RRID:AB_2340379, Donkey anti-goat, Cy3 (1:300) RRID:AB_2340411, Donkey anti-mouse, Cy3 (1:300) RRID:AB_2340813, RRID:AB_2340862, RRID:AB_2492288

Abstract

Huntington’s disease (HD) is a hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by severe neurodegeneration of the basal ganglia and neocortex. No cure is currently available, and new treatment options are urgently needed. Here, we show that the oligomer modifying molecule anle138b (INN: emrusolmin) improves multiple disease phenotypes in cell culture and in two mouse models of HD. Application of anle138b reduced mHTT aggregate formation and ameliorated neurotoxicity in primary neurons. Oral administration of anle138b delayed deposition of mHTT inclusions, reduced brain atrophy, mitigated neuroinflammation and transcriptional alterations, improved motor function and extended life span in HD mice. Downregulation of striatal markers and synapse loss in striatal spiny projection neurons were also partially rescued. No adverse effects of anle138b were observed in wildtype animals. Moreover, anle138b markedly decreased mHTT aggregation in human neural precursor cells differentiated from HD patient-derived induced pluripotent stem cells (iPSCs). Altogether these results illustrate the potential of anle138b as a disease-modifying treatment for HD.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

bioproject:PRJNA1429108, at NCBI BioProject; found in “Data availability”

Data availability

The RNA-seq dataset generated in this study is available in the following database: Sequence read archive (SRA), PRJNA1429108 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1429108)

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-026-00459-9 (https://www.ebi.ac.uk/biostudies/sourcedata/studies/S-SCDT-10_1038-S44321-026-00459-9).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 1 keyword, 11 MeSH terms, 1 funder, 76 references, 7 RRIDs.

Cite

This paper

da Silva Padilha, M., Koyuncu, S., Chabanis, E., Ryazanov, S., Leonov, A., Vilchez, D., Klein, R., Giese, A., Griesinger, C., & Dudanova, I. (2026). Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease. EMBO molecular medicine, 18(7), 2838-2866. https://doi.org/10.1038/s44321-026-00459-9

BibTeX

@article{dasilvapadilha2026anle138b, author = {da Silva Padilha, Miguel and Koyuncu, Seda and Chabanis, Evangeline and Ryazanov, Sergey and Leonov, Andrei and Vilchez, David and Klein, Rüdiger and Giese, Armin and Griesinger, Christian and Dudanova, Irina}, title = {{Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease}}, journal = {EMBO molecular medicine}, year = {2026}, month = jun, volume = {18}, number = {7}, pages = {2838--2866}, publisher = {Nature Publishing Group}, issn = {1757-4676}, doi = {10.1038/s44321-026-00459-9}, url = {https://doi.org/10.1038/s44321-026-00459-9}, pmid = {42362792}, pmcid = {PMC13365221} }

RIS

TY - JOUR AU - da Silva Padilha, Miguel AU - Koyuncu, Seda AU - Chabanis, Evangeline AU - Ryazanov, Sergey AU - Leonov, Andrei AU - Vilchez, David AU - Klein, Rüdiger AU - Giese, Armin AU - Griesinger, Christian AU - Dudanova, Irina TI - Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease T2 - EMBO molecular medicine J2 - EMBO Mol Med PY - 2026 DA - 2026/06/26 VL - 18 IS - 7 SP - 2838 EP - 2866 SN - 1757-4676 PB - Nature Publishing Group DO - 10.1038/s44321-026-00459-9 UR - https://doi.org/10.1038/s44321-026-00459-9 LA - en ER -

CSL-JSON

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