Development of novel inhibitors of C1q for the treatment of Neurodegenerative diseases

DESCRIPTION provided by applicant Alzheimerandapos s disease AD is the most common cause of dementia in the aging population and is a serious unmet medical social and economic problem worldwide Current therapies provide only modest symptomatic relief highlighting the need for better disease modifying treatments The goal is to advance a novel therapeutic agent ANX toward the clinic as a potential treatment for AD ANX inhibits C q the initiating molecule of the classical complement cascade C q has a critical role in the physical pruning of synapses during development In addition C q accumulates on synapses during normal aging at levels fold higher than those in younger animals Abnormal accumulation of C q may put synapses at risk of damage in a variety of neurodegenerative diseases leading to synapse loss and a decline in neurologic function It may also help to explain why age is the most important risk factor for neurodegenerative disease This work will seek to establish proof of concept that inhibition of C q will both protect against synapse loss and prevent functional decline in animal models of AD We will establish appropriate dosing regimens with ANX for chronic efficacy testing in mice as well as dose selection for safety evaluation in both rats and primates In order to achieve these goals over the course of studies ANX will be dosed in the range of mg Kg parenterally once weekly for durations of to months in a mouse models of AD Efficacy in behavioral endpoints that measure learning and memory such as the Morris water maze will be evaluated at the end of the dosing period Serum CSF and brain samples will be collected for biochemical and histological evaluation and levels of ANX in serum and CSF will be determined Target engagement of ANX will be evaluated by measuring C q levels in CSF and in hippocampal and cortical brain regions Efficacy will be evaluated by quantitative histology of pre and post synaptic markers to demonstrate impact on synapse protection and microglial and astrocytic activation Successful outcome of this work will allow advancement of ANX into early phase clinical studies within the next two years In addition to demonstration of efficacy in AD mouse models these preclinical studies will test on a fundamental level the hypothesis that preventing synapse loss can slow the progression of neurodegenerative disease and provide novel insights into the process of neurodegeneration PUBLIC HEALTH RELEVANCE Loss of synaptic connections in the brain during normal aging and in neurodegenerative disorders is associated with memory loss In this project we will test the efficacy and safety of an antibody that we hypothesize may block synapse loss in a mouse model of Alzheimerandapos s disease These studies will provide the critical in vivo proof of concept required to advance the antibody into human clinical trials