title: Poly(GP) proteins are a useful pharmacodynamic marker forC9ORF72-associated amyotrophic lateral sclerosis.
abstract: There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2repeat expansion in theC9ORF72gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role inC9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomaticC9ORF72mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2RNA and downstream G4C2RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2RNA-based therapies in symptomaticC9ORF72repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.
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mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000073885:C9orf72 Protein / Q000235:genetics*; D002460:Cell Line; D018900:Dinucleotide Repeats / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008137:Longitudinal Studies; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011379:Prognosis; D012313:RNA / Q000235:genetics
chemical_list: D015415:Biomarkers; D000073885:C9orf72 Protein; D016376:Oligonucleotides, Antisense; D012313:RNA