Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

Lien Nguyen; Fabio Montrasio; Amrutha Pattamatta; Solaleh Khoramian Tusi; Olgert Bardhi; Kevin D. Meyer; Lindsey Hayes; Katsuya Nakamura; Monica Banez-Coronel; Alyssa Coyne; Shu Guo; Lauren A. Laboissonniere; Yuanzheng Gu; Saravanakumar Narayanan; Benjamin Smith; Roger M. Nitsch; Mark W. Kankel; Mia Rushe; Jeffrey Rothstein; Tao Zu; Jan Grimm; Laura P.W. Ranum

doi:10.1016/j.neuron.2019.11.007

Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

Lien Nguyen, Fabio Montrasio, Amrutha Pattamatta, Solaleh Khoramian Tusi, Olgert Bardhi, Kevin D. Meyer, Lindsey Hayes, Katsuya Nakamura, Monica Banez-Coronel, Alyssa Coyne, Shu Guo, Lauren A. Laboissonniere, Yuanzheng Gu, Saravanakumar Narayanan, Benjamin Smith, Roger M. Nitsch, Mark W. Kankel, Mia Rushe, Jeffrey Rothstein, Tao ZuJan Grimm, Laura P.W. Ranum

School of Medicine

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

17 Scopus citations

Abstract

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA₁ interacts with TRIM21, and α-GA₁ treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA₁ reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA₁ is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

Original language	English (US)
Pages (from-to)	645-662.e11
Journal	Neuron
Volume	105
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2019.11.007
State	Published - Feb 19 2020

Keywords

BAC transgenic mice
C9orf72 ALS/FTD
G4C2 repeat expansion
RAN proteins
human antibody
immunotherapy
microsatellite expansion
proteasome and autophagy
protein co-aggregation
repeat associated non-ATG (RAN) translation

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2019.11.007

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Nguyen, L., Montrasio, F., Pattamatta, A., Tusi, S. K., Bardhi, O., Meyer, K. D., Hayes, L., Nakamura, K., Banez-Coronel, M., Coyne, A., Guo, S., Laboissonniere, L. A., Gu, Y., Narayanan, S., Smith, B., Nitsch, R. M., Kankel, M. W., Rushe, M., Rothstein, J., ... Ranum, L. P. W. (2020). Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron, 105(4), 645-662.e11. https://doi.org/10.1016/j.neuron.2019.11.007

Nguyen, L, Montrasio, F, Pattamatta, A, Tusi, SK, Bardhi, O, Meyer, KD, Hayes, L, Nakamura, K, Banez-Coronel, M, Coyne, A, Guo, S, Laboissonniere, LA, Gu, Y, Narayanan, S, Smith, B, Nitsch, RM, Kankel, MW, Rushe, M, Rothstein, J, Zu, T, Grimm, J & Ranum, LPW 2020, 'Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model', Neuron, vol. 105, no. 4, pp. 645-662.e11. https://doi.org/10.1016/j.neuron.2019.11.007

@article{6193b3c93c4b4e3e8f0c4e04804537d9,

title = "Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model",

abstract = "The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.",

keywords = "BAC transgenic mice, C9orf72 ALS/FTD, G4C2 repeat expansion, RAN proteins, human antibody, immunotherapy, microsatellite expansion, proteasome and autophagy, protein co-aggregation, repeat associated non-ATG (RAN) translation",

author = "Lien Nguyen and Fabio Montrasio and Amrutha Pattamatta and Tusi, {Solaleh Khoramian} and Olgert Bardhi and Meyer, {Kevin D.} and Lindsey Hayes and Katsuya Nakamura and Monica Banez-Coronel and Alyssa Coyne and Shu Guo and Laboissonniere, {Lauren A.} and Yuanzheng Gu and Saravanakumar Narayanan and Benjamin Smith and Nitsch, {Roger M.} and Kankel, {Mark W.} and Mia Rushe and Jeffrey Rothstein and Tao Zu and Jan Grimm and Ranum, {Laura P.W.}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2020",

month = feb,

day = "19",

doi = "10.1016/j.neuron.2019.11.007",

language = "English (US)",

volume = "105",

pages = "645--662.e11",

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T1 - Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

AU - Nguyen, Lien

AU - Montrasio, Fabio

AU - Pattamatta, Amrutha

AU - Tusi, Solaleh Khoramian

AU - Bardhi, Olgert

AU - Meyer, Kevin D.

AU - Hayes, Lindsey

AU - Nakamura, Katsuya

AU - Banez-Coronel, Monica

AU - Coyne, Alyssa

AU - Guo, Shu

AU - Laboissonniere, Lauren A.

AU - Gu, Yuanzheng

AU - Narayanan, Saravanakumar

AU - Smith, Benjamin

AU - Nitsch, Roger M.

AU - Kankel, Mark W.

AU - Rushe, Mia

AU - Rothstein, Jeffrey

AU - Zu, Tao

AU - Grimm, Jan

AU - Ranum, Laura P.W.

PY - 2020/2/19

Y1 - 2020/2/19

N2 - The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

AB - The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

KW - BAC transgenic mice

KW - C9orf72 ALS/FTD

KW - G4C2 repeat expansion

KW - RAN proteins

KW - human antibody

KW - immunotherapy

KW - microsatellite expansion

KW - proteasome and autophagy

KW - protein co-aggregation

KW - repeat associated non-ATG (RAN) translation

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DO - 10.1016/j.neuron.2019.11.007

M3 - Article

C2 - 31831332

AN - SCOPUS:85079230002

SN - 0896-6273

VL - 105

SP - 645-662.e11

JO - Neuron

JF - Neuron

IS - 4

ER -

Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

Abstract

Keywords

ASJC Scopus subject areas

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