. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med. 2017 Mar 29;9(383) PubMed.

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  1. Critics will argue that detection of poly-GP in the CSF of presymptomatic C9orf72 carriers by Gendron et al. and us (Lehmer et al., 2017) shows that DPR proteins play no role in C9ORF72 pathogenesis. In contrast, both groups of authors argue that expression of poly-GP (and presumably other DPR proteins) contributes to the morphological changes and measurable behavioral abnormalities detected in C9ORF72 carriers many years before meeting the diagnostic criteria for ALS or FTD (Rohrer et al., 2015). Regardless of the exact role in pathogenesis, measurement of poly-GP in the CSF is an excellent marker for repeat-directed therapeutic approaches. Gendron et al. use several in vitro and in vivo assays to convince us that poly-GP in the CSF represents DPR load in patients, because it seems to result from secretion of living cells rather than from passive release from dead neurons. Both reports use a similar MSD immunoassay. In the long run, our assay using only monoclonal antibodies could be more reproducible as a standardized test.

    Both papers find that poly-GP in CSF does not correlate with disease severity, age of onset, cognition, or other meaningful disease parameters. Gendron et al. find a non-significant increase in symptomatic versus asymptomatic patients and significantly higher poly-GP levels in male patients. In our smaller cohort, symptomatic and asymptomatic patients show very similar poly-GP levels, but female patients show ~1.7x higher signal than males (p=0.08). It’s puzzling that both cohorts show quite large, unexplained variability in poly-GP levels in C9ORF72 carriers, with several patients having very low poly-GP levels. It is possible that more sensitive single-molecule detection methods will show a clearer picture. Our analysis of poly-GP in control groups revealed an unexpected poly-GP signal in some AD but not in PD patients. So far, we cannot tell whether this signal in patients without C9ORF72 repeat expansion in peripheral blood derives from somatic mosaicism, other poly-GP coding repeat expansions, or (most likely) cross-reactivity with other CSF proteins. Next, we will analyze whether these poly-GP positive AD patients represent a meaningful disease subgroup.

    Taken together, poly-GP in the CSF is an excellent trait marker rather than a state marker for C9ORF72 disease that will be useful to address target engagement in future therapeutic trials as shown in a mouse model by Gendron et al. Additionally, neurofilaments should be measured to evaluate whether antisense therapy also restores axonal integrity (Lehmer et al. in press; Weydt et al., 2016; Mattson et al., 2017). 

    References:

    . Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD. EMBO Mol Med. 2017 Jul;9(7):859-868. PubMed.

    . Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol. 2015 Mar;14(3):253-62. Epub 2015 Feb 4 PubMed.

    . Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol. 2016 Jan;79(1):152-8. Epub 2015 Dec 17 PubMed.

    . Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 2017 May 1;74(5):557-566. PubMed.

    View all comments by Dieter Edbauer
  2. It is important to understand whether a drug is having the intended effect on its target as soon as possible after initiating experiments. A favorable result showing a decrease in poly(GP) proteins during a Phase 1 clinical trial would encourage starting the much more expansive Phase 2 and Phase 3 trials that are needed to evaluate whether a drug is effective in patients.

    In addition, Petrucelli and colleagues show that the poly(GP) marker can be reduced using antisense oligonucleotides (ASOs) that block expression of mutant C9ORF72. An ASO designed to treat spinal muscular atrophy was recently approved, demonstrating the potential of this class of drug to function in the central nervous system. Petrucelli’s results indicate that a similar strategy may be feasible for ALS. The findings smooth the way for clinical trials by suggesting poly(GP) proteins may be a convenient marker of such activity.

    View all comments by David Corey

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  1. Poly Dipeptide in Cerebrospinal Fluid Marks C9ORF72 Expansion Carriers