Prof. Dieter Edbauer, German Center for Neurodegenerative Diseases (DZNE); Prof. Christian Haass, German Center for Neurodegenerative Diseases (DZNE) and Ludwig-Maximilians-Universität München (LMU); Dr Kohji Mori, Ludwig-Maximilians-Universität München (LMU); Dr Thomas Arzberger, German Center for Neurodegenerative Diseases (DZNE) and Ludwig-Maximilians-Universität München (LMU); Dr Elisabeth Kremmer, Helmholtz Zentrum München
A (ggggcc)n hexanucleotide repeat expansion upstream of the coding region of C9orf72 is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Patients usually carry several hundred or thousand hexanucleotide repeats compared to less than 30 in the general population. The repeat expansion inhibits C9orf72 expression, and sense and antisense transcripts translated into five aggregating DRP proteins (poly-GA, -GP, -GR, -PA, -PR) may cause toxicity by sequestering RNA binding proteins in nuclear foci. It is postulated that toxic RNA and DPR proteins may trigger a deadly cascade with impairment of nuclear import and translational alterations leading to TDP-43 hyperphosphorylation, mislocalization (aggregation) and reduced excitability of neurons.
Monoclonal antibodies raised against the DPR showed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in patients with C9orf72 gene mutations. Treatment of primary neurons with anti-GA antibodies inhibits intracellular poly-GA aggregation and blocks the seeding activity of brain extracts from C9orf72 patients. In addition, a poly-DPR immunoassay from cerebrospinal fluid has been established to identify and characterize C9orf72 patients.
Inhibiting DPR protein generation or aggregation may prevent or delay disease progression in mutation carriers. Thus, anti-GA immunotherapy may be a future treatment option for C9orf72 ALS/FTLD.
We are currently testing active and passive vaccination against poly-GA in our transgenic mouse model expressing (GA)149-GFP from the Thy1 promoter. These mice show a progressive motor phenotype starting around 4 months of age and are well suited for testing poly-GA directed therapies.
We also aim to develop the antibody into a PET-ligand for longitudinal studies in patients. For this project we are currently testing smaller antibody fragments (e.g. scFv-CH3 minibodies). These ligands will be validated in the high-expressing poly-GA mice.
Patents are pending in US and EP.
Schludi et al. (2017), Acta Neuropathol 134(2):241-254; Zhou et al. (2017), EMBO Mol. Med. 9:687-702; Lehmer et al. (2017), EMBO Mol. Med. 9: 859-868; van Blitterswijk et al. (2015), Acta Neuropathol. 130: 863-876; Mackenzie et al. (2013), Acta Neuropathol. 126:859-879