Neutralizing RGMa with Elezanumab Promotes Cerebroprotection and Recovery in Rabbit Middle Cerebral Artery Occlusion

Translational Stroke Research, 2024 · DOI: https://doi.org/10.1007/s12975-023-01164-2 · Published: June 16, 2023

Simple Explanation

Repulsive guidance molecule A (RGMa) is an inhibitor of neuronal growth and survival which is upregulated in the damaged central nervous system following acute spinal cord injury (SCI), traumatic brain injury, acute ischemic stroke (AIS), and other neuropathological conditions. In this preclinical study, we evaluated whether elezanumab, a human anti-RGMa monoclonal antibody, could improve neuromotor function and modulate neuroinflammatory cell activation following AIS with delayed intervention times up to 24 h using a rabbit embolic permanent middle cerebral artery occlusion model (pMCAO). In two replicate 28-day pMCAO studies, weekly intravenous infusions of elezanumab, over a range of doses and TTIs of 6 and 24 h after stroke, significantly improved neuromotor function in both pMCAO studies when first administered 6 h after stroke.

Study Duration

28 days

Participants

Male New Zealand White rabbits weighing 2.8–3.6 kg

Evidence Level

Not specified

Key Findings

1
Elezanumab, administered 6 h after pMCAO, significantly reduced peak neuromotor deficits 48 h post stroke.
2
Both doses of elezanumab demonstrated a nearly identical efficacy response vs. IgG controls.
3
Significantly decreased Iba-1 intensity was associated with elezanumab treatment, suggesting attenuation of microglial activation and astrogliosis, even when the first dose was delayed 24 h post pMCAO.

Research Summary

These studies demonstrate that elezanumab administered 6 h after pMCAO enhanced recovery of neuromotor function and suppressed neuroinflammation and astrogliosis, which was also observed when elezanumab was first administered 24 h after pMCAO. These data support a putative cerebroprotective role for RGMa neutralization with elezanumab, potentially with a wider TTI than currently approved standards of care. In summary, these studies provide robust, reproducible, neuromotor, and histological evidence that neutralization of RGMa using elezanumab improves functional recovery and reduces neuroinflammation in an established experimental animal model of AIS.

Practical Implications

Broader Treatment Window

Elezanumab's extended TTI suggests potential to benefit a broader population of stroke patients beyond current therapies.

Novel Therapeutic Target

RGMa neutralization presents a unique mechanism of action distinct from current reperfusion strategies.

Clinical Trial Support

Preclinical findings support ongoing Phase 2 clinical trials evaluating elezanumab for acute ischemic stroke.

Study Limitations

1
Potential development of anti-drug antibodies (ADAs) in some animals.
2
Ex vivo MRI/DTI images did not clearly identify boundaries of suspected lesions.
3
Study focused on adult male rabbits without comorbidities, limiting generalizability.

Your Feedback

Was this summary helpful?

Back to Neurology