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Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo

Gene Therapy volume 31, pages 105–118 (2024)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72 gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72 mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.

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Fig. 1: Screening of artificial microRNA plasmid constructs in HEK293T cells and primary cultures of cortex from BAC112 transgenic mice.
Fig. 2: AAV9-delivered artificial microRNA amiRC9 silences C9ORF72 in the striatum of BAC112 transgenic mice.
Fig. 3: Suppression of C9ORF72 by AAV9-amiRC9 delivered ICV to neonatal BAC112 transgenic mice.
Fig. 4: Comparison of C9ORF72 suppression by temporal vein vs ICV injection of AAV-miRC9 in BAC112 transgenic mice.
Fig. 5: amiRC9 targets misspliced transcript, visualized by RNA in situ hybridization.
Fig. 6: Overview of the mechanism of action of amiRC9 to suppress C9ORF72 variants and decrease toxic dipeptide repeat proteins.

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The source data underlying Figs. 1c, e–h; 2b, c, e, f; 3b–d, f; 4b–d; 5c are provided as a Source Data file.

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Acknowledgements

We acknowledge G. Gao and Q. Su at University of Massachusetts Medical School who supervised the vector production. We thank Lorelei Stoica for training on all mouse surgeries, Lina Song for aiding with plasmid cloning and instruction, Qiushi Tang for assisting with vector constructs, Meghan Blackwood for aiding with tissue collections, Ozgun Uyan for scientific conversations and suggestions, and Allison Keeler for scientific conversations and editing the manuscript.

Funding

This study was supported by ALS Alliance Therapy (RHB), the ALS-FindingACure (RHB), and NINDS NS088689 (C.M. and RHB). RHB also received funding from the NINDS (NS079836), the ALS Association, ALSOne, the Angel Fund, the Cellucci Fund for ALS Research, the Michael Rosenfeld ALS Fund, the Pierre L. de Bourgknecht ALS Research Foundation, Project ALS and Target ALS.

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Author notes

  1. These authors contributed equally: Gabriela Toro Cabrera, Katharina E. Meijboom

  2. These authors jointly supervised this work: Robert H. Brown Jr, Christian Mueller.

Authors and Affiliations

  1. Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA

    Gabriela Toro Cabrera, Katharina E. Meijboom, Helene Tran, Zachariah Foster, Alexandra Weiss, Nicholas Wightman, Anthony Giampetruzzi & Robert H. Brown Jr

  2. Department of Pediatrics and Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA

    Gabriela Toro Cabrera, Katharina E. Meijboom, Abbas Abdallah, Rachel Stock, Alisha Gruntman & Christian Mueller

  3. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL, 32224, USA

    Tania Gendron & Leonard Petrucelli

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  1. Gabriela Toro Cabrera
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Contributions

GTC led design, analysis, interpretation of the study, and prepared the manuscript. Performed screenings, cultures, surgeries, ddPCR analysis, RNA FlSH and quantifications. KEM prepared manuscript for publication, did analyses and statistics and performed immunohistochemistry and microscopy experiments. AA aided with surgeries and temporal injections, primary cultures, scientific input, and editing. HT performed MSD ELISA assays for DPR detection, aided with scientific input. ZF performed animal tissue collection and sectioning including RNAscope quantification. AW managed the mice colony and aided with stereotaxic surgeries. NW performed Western blots for detection of C9ORF72 protein. RS performed cryosections of spinal cord and LCM microdissections. TG performed ELISA assays for DPR detection. AGr aided with temporal injections and manuscript editing. AGi aided with primary culture dissection. RHB and CM conceived of the project and supervised all aspects of its execution and analysis.

Corresponding authors

Correspondence to Robert H. Brown Jr or Christian Mueller.

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Competing interests

RHB and CM are inventors on the patent for the technology described within this report (rAAV-Based Compositions and Methods for Treating Amyotrophic Lateral Sclerosis, WO2015143078A1) and may be entitled to royalty payments in the future. The patent has been licensed to Apic-Bio for which CM and RHB are founders with equity. All other authors declare no competing financial interests.

Ethical approvals

All mouse experiments were conducted at UMass Medical School following protocols approved by the Institutional Review Board. The University of Massachusetts Medical School Institutional Animal Care and Use Committee approved all experiments involving animals.

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Cabrera, G.T., Meijboom, K.E., Abdallah, A. et al. Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo. Gene Ther 31, 105–118 (2024). https://doi.org/10.1038/s41434-023-00418-w

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