IL-1ra and CCL5, but not IL-10, are promising targets for treating SMA astrocyte-driven pathology.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Molecular Therapy Pub Date : 2024-12-12 DOI:10.1016/j.ymthe.2024.12.016
Reilly L Allison, Cecelia C Mangione, Mya Suneja, Jessica Gawrys, Brendan M Melvin, Natalya Belous, Megan LaCroix, Matthew Harmelink, Barrington G Burnett, Allison D Ebert
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引用次数: 0

Abstract

Spinal muscular atrophy (SMA) is a pediatric genetic disorder characterized by the loss of spinal cord motor neurons. Although the mechanisms underlying motor neuron loss are not clear, current data suggest that glial cells contribute to disease pathology. We have previously found that SMA astrocytes drive microglial activation and motor neuron loss potentially through the upregulation of NFkB-mediated pro-inflammatory cytokines. In this study, we tested the ability of neutralizing C-C motif chemokine ligand 5 (CCL5) while increasing either interleukin 10 (IL-10) or IL-1 receptor antagonist (IL-1ra) to reduce the pro-inflammatory phenotype of SMA astrocytes. While IL-10 was ineffective, IL-1ra ameliorated SMA astrocyte-driven glial activation and motor neuron loss in iPSC-derived cultures in vitro. In vivo AAV5 delivered IL-1ra overexpression and miR-30 shRNA knockdown of CCL5 had modest but significant improvements on lifespan, weight gain, motor neuron number, and motor function of SMNΔ7 mice. Together these data identify IL-1ra and CCL5 as possible therapeutic targets for SMA and highlight the importance of glial-targeted therapeutics for neurodegenerative disease.

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IL-1ra和CCL5,而非IL-10,是治疗SMA星形胶质细胞驱动的病理学的有希望的靶点。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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