Abstract Details

Title Inhibiting C1q Improves Compound Muscle Action Potential and Reduces Neuronal Damage in the SOD1G93A Mouse Model

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 11-004

Objective To determine if inhibiting C1q with anti-C1q antibodies could rescue neuronal damage and preserve synapses at the neuromuscular junction and protect muscle function in the SOD1^G93A mouse model of amyotrophic lateral sclerosis (ALS).

Background ALS is a sporadic or genetic disease associated with peripheral loss of synaptic connectivity at neuromuscular junctions and central loss of motor neurons. C1q, the initiating molecule of the classical complement cascade, marks synapses in the central nervous system for glial cell-mediated elimination during normal development, while triggering aberrant synapse loss in neurodegenerative disorders. In ALS, C1q additionally tags the neuromuscular junction within the peripheral nervous system prior to its removal by macrophages. The SOD1^G93A mouse model has been widely used to study a familial form of ALS. Despite data showing that embryonic knock out of C1q was not protective in a mutant SOD1 model, we hypothesized that excessive synaptic pruning initiated by C1q contributes to motor deficits in ALS and that pharmacologically inhibiting this process would be beneficial.

Design/Methods

We treated adult SOD1^G93A mice with an anti-C1q blocking antibody from 7 to 16 weeks of age. Treatment resulted in reduction of C1q in plasma, spinal cord, and muscle tissue, along with inhibition of downstream classical complement activation after 9 weeks of treatment.

Results Treated mice showed significant improvement in the amplitude as well as in reduced latency of compound muscle action potential, demonstrating increased synaptic connectivity at the neuromuscular junction upon C1q inhibition. Furthermore, anti-C1q treatment reduced neurofilament light chain levels in CSF and plasma of SOD1^G93A mice, marking the reduction in neuronal damage in this model.

Conclusions The data indicate that anti-C1q therapy preserves synapses of the neuromuscular junction and reduces neuronal damage in an ALS model. A phase 2 study of ANX005 anti-C1q therapy in patients with ALS is ongoing (clinicaltrials.gov NCT04569435).

Authors/Disclosures
Yaisa Andrews-zwilling (Annexon Biosciences) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Ted Yednock, PhD (Annexon Biosciences)	Ted Yednock, PhD has received personal compensation for serving as an employee of Annexon Inc. Ted Yednock, PhD has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Annexon Inc. Ted Yednock, PhD has stock in Annexon Inc. Ted Yednock, PhD has received intellectual property interests from a discovery or technology relating to health care.

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