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EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes
Cassandra Dennys1, Carlo Baggio2, Rochelle Rodrigo1
1Center for Gene Therapy, Nationwide Children's Hospital, 700 Children's Drive Columbus, OH 43205, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) is a degenerative disease that progressively destroys motor neurons (MNs). Earlier studies identified EphA4, a receptor tyrosine kinase, as a possible disease-modifying gene. The complex interplay between the EphA4 receptor and its ephrin ligands in motor neurons and astrocytes has not yet been fully elucidated and includes a putative pro-apoptotic activity of the unbound receptor compared to ephrin-bound receptor. We recently reported that astrocytes from patients with ALS induce cell death in co-cultured MNs. Here we found that first-generation synthetic EphA4 agonistic agent 123C4, effectively protected MNs when co-cultured with reactive astrocytes from patients with ALS from multiple subgroups (sALS and mutant SOD1). Newer generation and more potent EphA4 agonistic agents 150D4, 150E8, and 150E7 provided effective protection at a lower therapeutic dose. Combined, the data suggest that the development of EphA4 agonistic agents provides potentially a promising therapeutic strategy for patients with ALS.
Insights
New EphA4 agonists show promise for treating amyotrophic lateral sclerosis (ALS). These agents protected motor neurons from cell death induced by ALS patient astrocytes, suggesting a potential new therapy for ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Drug Discovery
Background:
- Amyotrophic lateral sclerosis (ALS) progressively destroys motor neurons.
- The EphA4 receptor tyrosine kinase is implicated in ALS pathogenesis.
- Astrocytes from ALS patients induce motor neuron cell death.
Purpose of the Study:
- To investigate the therapeutic potential of EphA4 agonistic agents in ALS.
- To evaluate the neuroprotective effects of EphA4 agonists against ALS-associated astrocyte-induced motor neuron death.
Main Methods:
- Co-culture of motor neurons with reactive astrocytes from ALS patients.
- Treatment with synthetic EphA4 agonistic agents (123C4, 150D4, 150E8, 150E7).
- Assessment of motor neuron survival and protection.
Main Results:
- First-generation EphA4 agonist 123C4 protected motor neurons from ALS astrocyte-induced death.
- Newer generation agonists (150D4, 150E8, 150E7) demonstrated enhanced potency and protection at lower doses.
- Protection was observed across different ALS subgroups, including sporadic ALS and mutant SOD1.
Conclusions:
- EphA4 agonistic agents represent a promising therapeutic strategy for ALS.
- Targeting the EphA4 pathway offers a potential avenue for neuroprotection in ALS.
- Further development of EphA4 agonists could lead to effective treatments for patients with ALS.
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