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Abstract Details

Inhibition of C1q Reduces Nerve Damage as Measured by Neurofilament Light Chain in the HD R6/2 Mouse Model
Movement Disorders
S36 - Movement Disorders: Clinical and Pathologic Characterization of Neurodegenerative Movement Disorders (1:36 PM-1:48 PM)
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HD is a neurodegenerative disorder caused by expansion of CAG repeats in the Huntingtin (HTT) gene. Increased expression of early classical complement components has been observed in striatal tissue from HD patients, and C1q has been implicated in neurodegeneration in HD mouse models.

To examine complement expression, neurodegeneration, and the potential therapeutic benefit of classical complement inhibition in an animal model for Huntington’s Disease (HD).

We used the R6/2 transgenic mouse model of HD and measured classical complement components in the plasma and cerebral spinal fluid (CSF) of transgenic vs. wild type mice. We measured the levels of neurofilament light chain (NfL) as a biomarker of neurodegeneration. To test the role of the classical complement pathway in neurodegeneration we pharmacologically blocked C1q activity, utilizing intraperitoneal administration of an anti-C1q blocking antibody (ANX-M1), and assessed NfL, motor behavioral function, and animal survival.
We found increased plasma levels of C1q and multiple complement components and an increased level of NfL in both plasma and CSF of R6/2 mice. There was a significant positive correlation between CSF NfL levels and plasma C1q, suggesting a potential role of the classical complement cascade in neurodegeneration. Treatment of animals with an anti-C1q monoclonal antibody fully blocked C1q in the plasma, normalized levels of complement components, significantly reduced CSF NfL levels, improved motor behavior, and increased R6/2 mouse survival.
This study suggests that inhibiting C1q protects against neurodegeneration in R6/2 mice and that C1q is a potential pharmacological target in HD. Administration of anti-C1q treatment significantly inhibited the classical complement pathway and reduced concentrations of C1q in the brain and plasma of R6/2 mice. A phase 2 study of ANX005 (humanized monoclonal antibody version of ANX-M1) anti-C1q therapy in HD patients is ongoing (clinicaltrials.gov NCT04514367).
Authors/Disclosures

PRESENTER
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Ted Yednock (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 received stock or an ownership interest from Annexon Inc. Ted Yednock, PhD has received intellectual property interests from a discovery or technology relating to health care.