AEV103

Chronic neuroinflammation drives the progression of neurodegeneration in neurodegenerative disorders including Parkinson’s disease (PD). Based on the pivotal role of neuroinflammation in neurodegeneration, immunomodulatory imide drugs (IMiDs) with anti-inflammatory actions have been considered and have shown potential to alleviate symptoms of PD and alter the course of disease progression. AEV103, a novel IMiD, potently mitigates neuroinflammation and provides efficacy in animal models of Alzheimer’s disease (AD), traumatic brain injury (TBI), stroke, and potentially PD and levodopa-induced dyskinesia.

Anti-neuroinflammatory, antioxidant and neuroprotective actions of AEV103 may rely on binding to cereblon (CRBN). Moreover, a CRBN-independent pathway regulating TNF-α expression potentiates the anti-inflammatory action of AEV103, as TNF-α provides a master switch that orchestrates the inflammatory response.

AEV103 is in the lead optimization process to maximize bioavailability for efficacy studies with oral administration. Non-GLP mammalian chromosome aberration/AMES fluctuation/hERG channel assays have been performed. CRBN-mediated biological actions are under investigation using a proteomics approach as the roles of CRBN are related to the stability of binding partners, and several IMiDs are known to regulate key neo-substrates of CRBN that impact measures of efficacy and potential adverse actions.

IMiDs can inhibit TNF-α generation independent of CRBN; however, growing evidence indicates that multiple biological actions of IMiDs are mediated via CRBN (Jung et al., 2020). AEV103 binds CRBN with greater affinity than FDA-approved IMiDs. Therefore, their mode of actions in mitigating pathogenesis of PD/AD/TBI/Stroke are hypothesized to be mainly via CRBN binding; however, they do not impact classical IMiD-CRBN downstream proteins associated with classical IMiD actions on cancer/teratogenicity (Lecca et al., 2022).

CRBN was originally identified as a gene causing human intellectual disability when mutated. It has a proposed role in cerebral tissue development, is expressed in hippocampus among other areas, and is associated with memory and learning processes (Choi et al., 2018). It is a well-known target protein of IMiDs underpinning their therapeutic anti-cancer effects. However, endogenous CRBN roles relate to inflammation, mitochondrial dysfunction and oxidative stress – all critical in pathogenesis of neurological disorders. CRBN mitigates TLR4 signaling (a target of LPS and α-Syn) by binding to TRAF6, TAK1, and c-jun (Min et al., 2016). CRBN regulates p62-mediated α-Syn aggregation. It also interacts with AMPK, GS, ClC-2, BKCa and p53, thereby regulating neuron excitability and survival (Moon et al., 2020). CRBN degrades CK-1 α to regulate Wnt signaling - a key player in dopaminergic neuron survival and protection (Shen et al., 2021).

AEV103 is protected under US Patent 8,927,725 that is in-licensed to Aevisbio from NIH to support its clinical development for treatment of neurodegenerative disorders.