A New Tool May Help Researchers Develop Potential Therapies for C9orf72 ALS

Engage. Make It So. A poly-GP assay, recently introduced by Dieter Edbauer’s laboratory, enables polyGP to be detected at high specificity (91.6%) and sensitivity (93.3%) using monoclonal antibodies – a key step in developing this assay for use in clinical trials. [Image: Lehmer et al., 2017, EMBO Molecular Medicine. Reproduced under a CC BY 4.0 license.]

A new tool is now available to ALS researchers worldwide. The monoclonal antibody, developed by Target ALS in New York, detects the dipeptide repeat protein poly-GP. The approach may help researchers create therapies for C9orf72 ALS by assessing target engagement (see April 2017 news).

The strategy is based on a sandwich ELISA assay, introduced by Tania Gendron, Leonard Petrucelli and colleagues at the Mayo Clinic in Jacksonville, Florida, which measures the levels of poly-GP in the CSF (see April 2017 news; Su et al., 2014). The assay is emerging as a potentially key strategy to evaluate RNA-targeted therapies being developed for C9orf72 ALS due to its ability to indirectly measure the impact of these potential treatments on the levels of repeat-rich C9orf72 RNAs (see March 2017 news; Gendron et al., 2017).

Efforts to create potential treatments for C9orf72 ALS are underway (see October 2017 news). One strategy, being developed by Wave Life Sciences in Cambridge, Massachusetts in collaboration with Robert Brown and colleagues at University of Massachusetts Medical School, aims to protect motor neurons in ALS by reducing levels of repeat-rich C9orf72 RNAs with antisense oligonucleotides (see May 2018 conference news). A clinical trial is anticipated to begin as early as the end of 2018.


Gendron TF, Chew J, Stankowski JN, Hayes LR, Zhang YJ, Prudencio M, Carlomagno Y, Daughrity LM, Jansen-West K, Perkerson EA, O’Raw A, Cook C, Pregent L, Belzil V, van Blitterswijk M, Tabassian LJ, Lee CW, Yue M, Tong J, Song Y, Castanedes-Casey M, Rousseau L, Phillips V, Dickson DW, Rademakers R, Fryer JD, Rush BK, Pedraza O, Caputo AM, Desaro P, Palmucci C, Robertson A, Heckman MG, Diehl NN, Wiggs E, Tierney M, Braun L, Farren J, Lacomis D, Ladha S, Fournier CN, McCluskey LF, Elman LB, Toledo JB, McBride JD, Tiloca C, Morelli C, Poletti B, Solca F, Prelle A, Wuu J, Jockel-Balsarotti J, Rigo F, Ambrose C, Datta A, Yang W, Raitcheva D, Antognetti G, McCampbell A, Van Swieten JC, Miller BL, Boxer AL, Brown RH, Bowser R, Miller TM, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Traynor BJ, Disney MD, Benatar M, Silani V, Glass JD, Floeter MK, Rothstein JD, Boylan KB, Petrucelli L. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med. 2017 Mar 29;9(383). [PubMed].

Lehmer C, Oeckl P, Weishaupt JH, Volk AE, Diehl-Schmid J, Schroeter ML, Lauer M, Kornhuber J, Levin J, Fassbender K, Landwehrmeyer B; German Consortium for Frontotemporal Lobar Degeneration., Schludi MH, Arzberger T, Kremmer E, Flatley A, Feederle R, Steinacker P, Weydt P, Ludolph AC, Edbauer D, Otto M.Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD. EMBO Mol Med. 2017 Apr 13. pii: e201607486. [PubMed]

Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, Johnston A, Overstreet K, Oh SY, Todd PK, Berry JD, Cudkowicz ME, Boeve BF, Dickson D, Floeter MK, Traynor BJ, Morelli C, Ratti A, Silani V, Rademakers R, Brown RH, Rothstein JD, Boylan KB, Petrucelli L, Disney MD. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron. 2014 Sep 3;83(5):1043-50. [PubMed].


c9orf72 disease-als poly-GP target engagement topic-preclinical topic-randd
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