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Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington's disease
Miguel da Silva Padilha1,2,3, Seda Koyuncu3,4, Evangeline Chabanis1
1Center for Anatomy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Insights
Anle138b, a novel molecule, shows promise in treating Huntington's disease (HD). It reduces toxic protein aggregates and improves symptoms in cell and animal models, offering hope for a new therapy.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder.
- It results from CAG repeat expansion in the huntingtin gene, leading to mutant huntingtin (mHTT) aggregates.
- Current treatments for HD are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic potential of anle138b (emrusolmin) in Huntington's disease.
- To evaluate anle138b's effects on mHTT aggregation, neurotoxicity, and disease phenotypes.
Main Methods:
- Utilized cell culture models, primary neurons, and two mouse models of HD.
- Administered anle138b orally to assess its impact on disease progression.
- Examined mHTT aggregate formation, neuroinflammation, brain atrophy, motor function, and lifespan.
- Investigated anle138b's effects on human neural precursor cells derived from HD patient iPSCs.
Main Results:
- Anle138b reduced mHTT aggregate formation and neurotoxicity in neuronal cultures.
- Oral anle138b administration delayed mHTT inclusion deposition and reduced brain atrophy in HD mice.
- Anle138b mitigated neuroinflammation, transcriptional alterations, and synapse loss in HD mouse models.
- The compound improved motor function and extended lifespan in HD mice without adverse effects in wildtype animals.
- Anle138b decreased mHTT aggregation in iPSC-derived cells from HD patients.
Conclusions:
- Anle138b demonstrates significant efficacy in improving multiple Huntington's disease phenotypes across various models.
- The molecule effectively reduces toxic mHTT aggregates and ameliorates key pathological features of HD.
- Anle138b presents a promising candidate for a disease-modifying treatment for Huntington's disease.
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.
