Citations 2
Blocking RAN translation without altering repeat RNAs rescues C9ORF72 -related ALS and FTD phenotypes
Jiang, Xin , Schaeffer, Laure, Patni, Divya, Russo, Tommaso , Lee, Chao-Zong, Aguilar, Corey, Marques, Christine , Jansen-West, Karen, Hruška-Plocháň, Marián , Ray-Soni, Ananya, Lim, Su Min , Held, Aaron , Yue, Mei, Otero, Paula Castellanos, Aryal, Sandeep , Beaussant, Hortense D. A. M. , Basu, Himanish , Takakuwa, Hiro , Daughrity, Lillian M. , Ramesh, Nandini , Costa, Paulo J. da, Quadros, Ana Rita A. A., Nolan, Matthew , Reyes, Charles Jourdan , Wheeler, Hayden J., Moran, Laura C. , Griesman, Grant , Wymann, Benjamin , Trombetta, Bianca A. , Lopez-De-Silanes, Emma Sofia , Canori, Michael, Silva, Yasmim Vieira Souza Da, Eriani, Gilbert , Albers, Mark W. , Arnold, Steven E. , Song, Yuyu , Jain, Ankur, Chiu, I., Zhang, Yong-Jie, Gao, Fen‐Biao , Wainger, Brian J. , Polymenidou, Magdalini , Petrucelli, Leonard, Martin, Franck , Lagier-Tourenne, Clotilde, Lagier‐Tourenne, Clotilde , Jansen-West, Karen R , Castellanos Otero, Paula, Da Costa, Paulo , A A Quadros, Ana Rita , Eriani, Gilbert , Albers, Mark W , Arnold, Steven E , Song, Yuyu , Chiu, Isaac M , Zhang, Yong-Jie , Gao, Fen-Biao , Wainger, Brian J , Polymenidou, Magdalini , Petrucelli, Leonard , Martin, Franck , Lagier-Tourenne, Clotilde , Lee, Chao-Zong , Jansen‐West, Karen , Ray-Soni, Ananya, Krishnan, Gopinath , Jain, Ankur , Petrucelli, Leonard
Science | February 5, 2026 | Volume: 391 | Issue: 6785 | Pages: No page available
GGGGCC (G 4 C 2 ) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43 inclusions, STING activation, motor neuron loss, neuroinflammation, and increased plasma neurofilament concentration, were alleviated in C9ORF72 mice. Base editing of the CUG codon also improved molecular phenotypes and survival in patient induced pluripotent stem cell–derived neurons, which highlights the potential of therapeutically targeting DPR production rather than repeat RNAs.
Comprehensive evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9orf72 disease
Jambeau, Mélanie, Meyer, Kevin D. , Tabet, Ricardos, Lee, Chao-Zong , Ray-Soni, Ananya, Aguilar, Corey, Savage, Kitty, Mishra, Nibha, Cavegn, Nicole, Borter, Petra, Lin, Chun-Chia , Jansen‐West, Karen , Freyermuth, Fernande, Pérez‐Berlanga, Manuela , Jiang, Xin, Daughrity, Lilian M., Pereira, João D. , Narayanan, Sarav, Gu, Yuanzheng , Dhokai, Shekhar, Dalkilic-Liddle, Isin, Maniecka, Zuzanna, Weber, Julien, McAlonis‐Downes, Melissa , Berezovski, Eugene, Zhang, Yong-Jie, Wainger, Brian J. , Kankel, Mark W. , Rushe, Mia, Höck, Christoph, Nitsch, Roger M., Cleveland, Don W. , Petrucelli, Leonard , Polymenidou, Magdalini , Lagier‐Tourenne, Clotilde , Zhang, Yong‐Jie , Zhang, Yong-Jie , Lagier-Tourenne, Clotilde , Jiang, Xin , Zhang, Yong-Jie , Hruška-Plocháň, Marián , Ray-Soni, Ananya, Mishra, Nibha, Li, Nan , Rossi, Pierre De , Daughrity, Lilian M., Workman, Michael J. , Berry, James D. , Gendron, Tania F. , Montrasio, Fabio , Grimm, Jan
Proceedings of the National Academy of Sciences | December 1, 2022 | Volume: 119 | Issue: 49 | Pages: No page available
Hexanucleotide G 4 C 2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G 4 C 2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72 450 mice. However, chronic administration of anti-GA antibodies in AAV-(G 4 C 2 ) 149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.