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

Gabriela Toro Cabrera; Katharina E. Meijboom; Abbas Abdallah; Helene Tran; Zachariah Foster; Alexandra Weiss; Nicholas Wightman; Rachel Stock; Tania Gendron; Alisha Gruntman; Anthony Giampetruzzi; Leonard Petrucelli; Robert H. Brown; Christian Mueller

doi:10.1038/s41434-023-00418-w

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

Gabriela Toro Cabrera, Katharina E. Meijboom, Abbas Abdallah, Helene Tran, Zachariah Foster, Alexandra Weiss, Nicholas Wightman, Rachel Stock, Tania Gendron, Alisha Gruntman, Anthony Giampetruzzi, Leonard Petrucelli, Robert H. Brown, Christian Mueller

Neuroscience

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	105-118
Number of pages	14
Journal	Gene Therapy
Volume	31
Issue number	3-4
DOIs	https://doi.org/10.1038/s41434-023-00418-w
State	Published - Mar 2024

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics

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Cabrera, G. T., Meijboom, K. E., Abdallah, A., Tran, H., Foster, Z., Weiss, A., Wightman, N., Stock, R., Gendron, T., Gruntman, A., Giampetruzzi, A., Petrucelli, L., Brown, R. H., & Mueller, C. (2024). Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo. Gene Therapy, 31(3-4), 105-118. https://doi.org/10.1038/s41434-023-00418-w

Cabrera, GT, Meijboom, KE, Abdallah, A, Tran, H, Foster, Z, Weiss, A, Wightman, N, Stock, R, Gendron, T, Gruntman, A, Giampetruzzi, A, Petrucelli, L, Brown, RH & Mueller, C 2024, 'Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo', Gene Therapy, vol. 31, no. 3-4, pp. 105-118. https://doi.org/10.1038/s41434-023-00418-w

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title = "Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo",

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.",

author = "Cabrera, {Gabriela Toro} and Meijboom, {Katharina E.} and Abbas Abdallah and Helene Tran and Zachariah Foster and Alexandra Weiss and Nicholas Wightman and Rachel Stock and Tania Gendron and Alisha Gruntman and Anthony Giampetruzzi and Leonard Petrucelli and Brown, {Robert H.} and Christian Mueller",

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year = "2024",

month = mar,

doi = "10.1038/s41434-023-00418-w",

language = "English (US)",

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AU - Cabrera, Gabriela Toro

AU - Meijboom, Katharina E.

AU - Abdallah, Abbas

AU - Tran, Helene

AU - Foster, Zachariah

AU - Weiss, Alexandra

AU - Wightman, Nicholas

AU - Stock, Rachel

AU - Gendron, Tania

AU - Gruntman, Alisha

AU - Giampetruzzi, Anthony

AU - Petrucelli, Leonard

AU - Brown, Robert H.

AU - Mueller, Christian

PY - 2024/3

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N2 - 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.

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

Abstract

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