C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration
Ted Yednock1, Donald S Fong2, Eleonora M Lad3
1Annexon Biosciences, 1400 Sierra Point Parkway Building C, 2nd Floor, Brisbane, CA, 94005, USA.
Insights
Targeting the classical complement pathway, specifically C1q, may offer a novel therapeutic strategy for geographic atrophy (GA) in age-related macular degeneration (AMD). This approach shows promise for neuroprotection and improved efficacy in preclinical models.
Area of Science:
- Ophthalmology
- Immunology
- Neuroscience
Background:
- Geographic atrophy (GA) is a neurodegenerative disorder of the retina linked to age-related macular degeneration (AMD).
- The complement system is implicated in AMD pathogenesis, but the specific roles of its pathways (classical, lectin, alternative) remain unclear.
- C1q, the initiator of the classical complement pathway, is increasingly recognized as a significant factor in AMD progression.
Purpose of the Study:
- To investigate the role of the classical complement pathway, particularly C1q, in the pathogenesis of geographic atrophy (GA).
- To evaluate the potential of targeting C1q or the classical pathway as a therapeutic strategy for GA associated with AMD.
Main Methods:
- Analysis of human genetic data and pre-clinical studies supporting the complement system's role in AMD.
- Examination of C1q expression and localization in relation to disease progression.
- Assessment of photoreceptor cell damage in mouse models with genetic C1q or C4 deletion, or local C1q inhibition.
Main Results:
- C1q is expressed by infiltrating cells and accumulates with disease progression, particularly at photoreceptor synapses.
- Accumulation of C1q correlates with synapse elimination and neurodegeneration.
- Genetic deletion of C1q or C4, and local C1q inhibition, protected photoreceptor cells in mouse models.
Conclusions:
- The classical complement pathway, driven by C1q, plays a critical role in GA pathogenesis.
- Targeting C1q or the classical pathway presents a specific and potentially effective therapeutic strategy for GA.
- This approach may offer improved efficacy and safety compared to broader complement inhibition strategies.
Abstract:
Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a retinal neurodegenerative disorder. Human genetic data support the complement system as a key component of pathogenesis in AMD, which has been further supported by pre-clinical and recent clinical studies. However, the involvement of the different complement pathways (classical, lectin, alternative), and thus the optimal complement inhibition target, has yet to be fully defined. There is evidence that C1q, the initiating molecule of the classical pathway, is a key driver of complement activity in AMD. C1q is expressed locally by infiltrating phagocytic cells and C1q-activating ligands are present at disease onset and continue to accumulate with disease progression. The accumulation of C1q on photoreceptor synapses with age and disease is consistent with its role in synapse elimination and neurodegeneration that has been observed in other neurodegenerative disorders. Furthermore, genetic deletion of C1q, local pharmacologic inhibition within the eye, or genetic deletion of downstream C4 prevents photoreceptor cell damage in mouse models. Hence, targeting the classical pathway in GA could provide a more specific therapeutic approach with potential for favorable efficacy and safety.
