I11 Pharmacologic inhibition of the classical complement pathway enhances neuronal function and HD R6/2 mouse survival

Abstract

<h3>Background</h3> Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats in the Huntingtin (HTT) gene. <h3>Aim</h3> There is human evidence of increased complement biosynthesis and activation in HD, with increased immunoreactivity for C1q, C4, C3 and C3b observed in striatal neurons, astrocyte, and microglia cells. However, the role of the classical pathway in HD pathogenesis is unclear. <h3>Methods</h3> Using the R6/2 mouse model of HD with ~ 120 CAG expansion, we investigated alteration of classical complement cascade in plasma and cerebral spinal fluid (CSF), we evaluated correlation of classical complement C1q levels with the neurodegenerative biomarker Neurofilament Light Chain (NFL) levels and assessed efficacy of anti C1q mAb therapy in preventing neurodegeneration and ameliorating disease progression. <h3>Results</h3> We found evidence of perturbations in the complement pathway, such as significant increase in plasma levels of C1q, C1s, C4, C3 and C3d during disease progression. Positive correlation of plasma C1q with CSF NFL levels was observed, suggesting a role of the classical complement cascade in neurodegeneration and disease progression. To test this hypothesis, we pharmacologically inhibited the classical pathway via systemic administration of anti-C1q mAb (ANX-M1, Annexon Biosciences). We observed that reduction of free C1q by anti C1q mAb therapy resulted in normalized complement pathway activity, reduced levels of CSF NFL, improved motor behavior measured with the open field assay and improved R6/2 mouse survival. <h3>Conclusions</h3> Altogether this study suggests that inhibiting C1q restores synaptic and neuronal health in mice with expanded CAG repeats in the HTT gene and C1q is a potential pharmacological target in HD. A Phase 2 study of ANX005 anti-C1q therapy in HD patients (clinical trials.gov NCT04514367) is ongoing.