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.]

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.”

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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.

References

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