Scientists Target Engagement in Future C9orf72 ALS Clinical Trials

Consult polyGP? The dipeptide repeat protein polyGP may help clinicians evaluate potential therapies for C9orf72 ALS by enabling the monitoring of target engagement and the pharmacodynamic response. [Reprinted with permission from Gendron et al., 2017, Science Translational Medicine, AAAS.]

An emerging biomarker may facilitate testing of potential therapies for C9orf72 ALS according to a new study led by Mayo Clinic’s Leonard Petrucelli in Florida. The study found that C9orf72 ALS patient-derived neurons pre-treated with antisense oligonucleotides targeting C9orf72 repeat expansions (C9orf72 ASOs) exhibited a dose-dependent decrease of polyGP. What’s more, the researchers saw a similar dose-dependent decrease in this C9orf72-associated dipeptide repeat protein in CSF which correlated with a drop in C9orf72 expanded repeat RNAs in the brain of a C9orf72 ASO-treated mouse model of the disease.

Together, the results suggest that polyGP may help researchers evaluate potential treatment strategies for C9orf72 ALS in the clinic by monitoring target engagement. The approach is based on an antibody-based “sandwich” assay previously developed by the Petrucelli lab that detects polyGP (see August 2014 news; Su et al., 2014). The ELISA assay enables the dipeptide repeat protein, which is the most soluble in CSF, to be detected in people with the disease.

The study appeared on March 29 in Science Translational Medicine.

Targeting engagement? A new polyGP assay, recently introduced by German Center for Neurodegenerative Diseases’ 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. The assay can detect polyGP in people at risk of developing C9orf72 ALS, suggesting this assay may also be useful in diagnosing the disease. [Lehmer et al., 2017; Reproduced under a CC BY 4.0 license.]

Meanwhile, researchers at Biogen in Cambridge, MA and Ionis Pharmaceuticals in Carlsbad, California are gearing up to evaluate C9orf72 ASOs at the phase 1 stage.  The potential treatment strategy aims to slow the progression of C9orf72 ALS by reducing levels of potentially toxic C9orf72 expanded repeat RNAs (see October 2013May 2016 news; Jiang et al., 2016; Sareen et al., 2013Donnelly et al., 2013).  The RNAs are thought to contribute to motor neuron toxicity at least in part, by sequestering essential RNA-binding proteins (Lagier-Tourenne et al., 2013). The strategy also aims to lower the levels of C9orf72 dipeptide repeat proteins in the CNS by reducing their future synthesis. The approach is one of at least two being developed against the disease (see February 2017 news).

The potential treatment strategy is rapidly approaching the clinic.  The clinical trial protocol is still to be announced.  But according to Biogen’s Steve Han, the study plans to measure levels of polyGP in combination with several emerging biomarkers of neurodegeneration. The approach, according to Han, will facilitate the evaluation of this strategy by enabling monitoring of target engagement and the pharmacodynamic response.

“We are excited about the emerging biomarkers available to ensure at an early stage of clinical development that we are on the right track,” said Han. “We are eager to progress this approach to patient trials soon.”


To learn more about polyGP, including its potential for the diagnosis and developing treatments for ALS, check out the March 2017 news feature Poly Dipeptide in Cerebrospinal Fluid Marks C9ORF72 Expansion Carriers.


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].

Jiang J, Zhu Q, Gendron TF, Saberi S, McAlonis-Downes M, Seelman A, Stauffer JE, Jafar-Nejad P, Drenner K, Schulte D, Chun S, Sun S, Ling SC, Myers B, Engelhardt J, Katz M, Baughn M, Platoshyn O, Marsala M, Watt A, Heyser CJ, Ard MC, De Muynck L, Daughrity LM, Swing DA, Tessarollo L, Jung CJ, Delpoux A, Utzschneider DT, Hedrick SM, de Jong PJ, Edbauer D, Van Damme P, Petrucelli L, Shaw CE, Bennett CF, Da Cruz S, Ravits J, Rigo F, Cleveland DW, Lagier-Tourenne C. Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs. Neuron. 2016 May 4;90(3):535-50. [PubMed].

Sareen D, O’Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, Gendron T, Petrucelli L, Baughn M, Ravits J, Harms MB, Rigo F, Bennett CF, Otis TS, Svendsen CN, Baloh RH. Targeting RNA Foci in iPSC-Derived Motor Neurons from ALS Patients with a C9ORF72 Repeat Expansion. Sci Transl Med. 2013 Oct 23;5(208):208ra149. [PubMed].

Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013 Oct 16;80(2):415-28. [PubMed].

Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR, Jiang J, Watt AT, Chun S, Katz M, Qiu J, Sun Y, Ling SC, Zhu Q, Polymenidou M, Drenner K, Artates JW, McAlonis-Downes M, Markmiller S, Hutt KR, Pizzo DP, Cady J, Harms MB, Baloh RH, Vandenberg SR, Yeo GW, Fu XD, Bennett CF, Cleveland DW, Ravits J. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4530-9. [PubMed]


antisense c9orf72 disease-als disease-ftd target engagement topic-biomarkers topic-clinical topic-randd
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