Targeting Inflammasome Mediated Neuronal-Microglial Crosstalk as a Therapeutic Substrate in c9orf72 FTD/ALS

James J Peters Va Medical Center, Bronx NY

Investigators

Abstract

ABSTRACT Of the various genetic causes of familial Amyotrophic Lateral Sclerosis (ALS), repeat expansions of the G4C2 promoter of C9orf72 account for ~40% of the cases, while the same mutations accounts for 18% of familial Frontotemporal Dementia (FTD) cases. Clinical overlap exists between the two disorders as the frequency of FTD symptoms can be detected in up to 50% of ALS patients. The prevalence of ALS and FTD symptomatic overlap is far greater in patients with repeat expansions in the G4C2 of C9orf72 than in patients with sporadic forms of ALS, the rate of disease progression in C9orf72 positive patients is also more rapid. Such overlap in clinical symptoms suggest C9orf72 mutations recruit related pathophysiological pathways responsible for overlapping neuropathological manifestations in ALS and FTD. Of the various risk factors for the development of FTD/ALS, military service significantly increases the odds ratio for the diagnosis of FTD/ALS in military veterans compared to non-military personnel. Veterans are uniquely vulnerable to the development of FTD/ALS due to its correlation with traumatic brain injury (TBI), compared to other types of dementias13. The overarching goal of this proposal, entitled “Targeting inflammasome mediated neuronal-microglial crosstalk as a therapeutic substrate in c9orf72 FTD/ALS”, is to evaluate the therapeutic efficacy of targeting CXCL10 induced neuroinflammation in vivo in a model of c9orf72 frontotemporal dementia- amyotrophic lateral sclerosis with Eldelumab, a CXCL10 neutralizing antibody. We utilize a well- established and characterized model containing 100 repeats of the dipeptide repeat protein (DPR) Glycine- Arginine (GR). Our feasibility studies suggest that neurons expressing GFP-(GR)100 release stress signals, including CXCL10. CXCL10 induces NLRP3 inflammasome activation, thereby promoting the release of proinflammatory IL-1β and IL-18. Genetic ablation of the NLRP3 inflammasome attenuated mortality, motor function, anxiety, and contextual memory, in vivo. The proposed studies will evaluate targeting CXCL10 mediated neuroinflammation as a therapeutic intervention. Furthermore, we will evaluate the presence of this crosstalk mechanism in vivo in models of other causes of genetic FTD/ALS. To test the utility of targeting this mechanism presymptomatically/symptomatically, through the utilization of mouse models with Designer Receptors Exclusively Activated by Designer Drugs (DREADD) coupled to the CXCR3 receptor on microglia in the models of FTD/ALS we will investigate the effects of targeting CXCL10 (regardless of cellular source). Finally, we will evaluate the efficacy of Eldelumab, an anti-CXCL10 monoclonal antibody, which has been previously clinically trialed for Crohn's disease, ulcerative colitis, and rheumatoid arthritis, with a known human safety profile. Collectively, these innovative studies will evaluate the efficacy of targeting CXCL10 as a treatment for FTD/ALS, further characterize the role of neuroinflammation in the pathogenesis of the disease, and evaluate the ability of Eldelumab to be employed as a therapeutic. We appreciate the significance of sex consideration in the interpretation and generalizability of scientific results, therefore, to achieve rigorous and translatable results, we will perform analyses on balanced samples of male and female mice, providing data disaggregated by sex, as well as grouped by sex. Our secondary analyses in the GFP- (GR)100 model of ALS/FTD have suggested both male and female mice are susceptible to impairment in our assessed behavioral paradigm.