Potent and Selective EphA4 Agonists for the Treatment of ALS

Wu, Bainan; De, Surya K.; Kulinich, Anna; Salem, Ahmed F.; Koeppen, Jordan; Wang, Rengang; Barile, Elisa; Wang, Si; Zhang, Dongxiang; Ethell, Iryna M.; Pellecchia, Maurizio

doi:10.1016/j.chembiol.2017.01.006

Cited by 47 publications

(59 citation statements)

References 43 publications

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“…Motor neuron-specific EphA4 knockdown or the use of an EphA4-blocking recombinant protein administered systemically, had a moderate effect on disease onset in the same model 20,21 . In contrast, the systemic administration of an EphA4-specific agonist improved the survival of SOD1 G93A mice 22 . Therefore, there is a need for additional approaches to better understand the modifying role of EphA4 in ALS.…”

Section: Introductionmentioning

confidence: 86%

Reducing EphA4 before disease onset does not affect survival in a mouse model of Amyotrophic Lateral Sclerosis

Rué

Timmers

Lenaerts

et al. 2019

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons resulting in severe neurological symptoms. Previous findings of our lab suggested that the axonal guidance tyrosine-kinase receptor EphA4 is an ALS disease-modifying gene. Reduction of EphA4 from developmental stages onwards rescued a motor neuron phenotype in zebrafish, and heterozygous deletion before birth in the SOD1G93A mouse model of ALS resulted in improved survival. Here, we aimed to gain more insights in the cell-specific role of decreasing EphA4 expression in addition to timing and amount of EphA4 reduction. To evaluate the therapeutic potential of lowering EphA4 later in life, we ubiquitously reduced EphA4 levels to 50% in SOD1G93A mice at 60 days of age, which did not modify disease parameters. Even further lowering EphA4 levels ubiquitously or in neurons, did not improve disease onset or survival. These findings suggest that lowering EphA4 as target in ALS may suffer from a complex therapeutic time window. In addition, the complexity of the Eph-ephrin signalling system may also possibly limit the therapeutic potential of such an approach in ALS. We suggest here that a specific EphA4 knockdown in adulthood may have a limited therapeutic potential for ALS.

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Section: Introductionmentioning

confidence: 86%

Reducing EphA4 before disease onset does not affect survival in a mouse model of Amyotrophic Lateral Sclerosis

Rué

Timmers

Lenaerts

et al. 2019

Sci Rep

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show abstract

“…When receptor and ligand interact, bidirectional signalling occurs downstream of both Ephs and ephrins, giving rise to attractive or repulsive stimuli of two opposing cell membranes [34]. Although the role of EphA4 ligands in ALS is unknown, an EphA4 agonist that impedes EphA4 binding to its ligands, and an EphA4-Fc recombinant protein that reduces binding of EphA4 ligands to the receptor beneficially affected the phenotypes in mouse models for ALS [44, 47].…”

Section: Introductionmentioning

confidence: 99%

Reduction of ephrin-A5 aggravates disease progression in amyotrophic lateral sclerosis

Rué

Oeckl

Timmers

et al. 2019

acta neuropathol commun

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brainstem, spinal cord and motor cortex. ALS is characterized by genetic and clinical heterogeneity, suggesting the existence of genetic factors that modify the phenotypic expression of the disease. We previously identified the axonal guidance EphA4 receptor, member of the Eph-ephrin system, as an ALS disease-modifying factor. EphA4 genetic inhibition rescued the motor neuron phenotype in zebrafish and a rodent model of ALS. Preventing ligands from binding to the EphA4 receptor also successfully improved disease, suggesting a role for EphA4 ligands in ALS. One particular ligand, ephrin-A5, is upregulated in reactive astrocytes after acute neuronal injury and inhibits axonal regeneration. Moreover, it plays a role during development in the correct pathfinding of motor axons towards their target limb muscles. We hypothesized that a constitutive reduction of ephrin-A5 signalling would benefit disease progression in a rodent model for ALS. We discovered that in the spinal cord of control and symptomatic ALS mice ephrin-A5 was predominantly expressed in neurons. Surprisingly, reduction of ephrin-A5 levels in SOD1 G93A mice accelerated disease progression and reduced survival without affecting disease onset, motor neuron numbers or innervated neuromuscular junctions in symptomatic mice. These findings suggest ephrin-A5 as a modifier of disease progression that might play a role in the later stages of the disease. Similarly, we identified a more aggressive disease progression in patients with lower ephrin-A5 protein levels in the cerebrospinal fluid without modifying disease onset. In summary, we identified reduced expression of ephrin-A5 to accelerate disease progression in a mouse model of ALS as well as in humans. Combined with our previous findings on the role of EphA4 in ALS our current data suggests different contribution for various members of the Eph-ephrin system in the pathophysiology of a motor neuron disease. Electronic supplementary material The online version of this article (10.1186/s40478-019-0759-6) contains supplementary material, which is available to authorized users.

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“…While beneficial effects were seen in SOD1 G93A mice treated with an EphA4 ectodomain fused to Fc approach for inhibiting EphA4 8 , the complexities of multiple ephrin ligands that are shared between EphA4 and other ephrin receptors as well as of potential differential effects of forward and reverse ephrin-EphA receptor signaling make it hard to confirm a role for EphA4 inhibition in that study. Complexities about how to target EphA4 are also raised by the report that a compound acting as an agonist when tested in in vitro assays prolongs survival in SOD1 G93A mice 7 . Notably that study, which rigorously characterized EphA4 ligands, found no binding of the putative EphA4 inhibitors, compound 1, and rhynchophylline to EphA4 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…The identification of a protective role for EphA4 reduction in ALS models, along with evidence suggesting EphA4 inhibition could be protective in mouse models of Alzheimer’s disease, spinal cord injury, and stroke 3 – 6 , prompted interest in developing EphA4 inhibitors as a potential therapeutic strategy for treating neurodegeneration. Subsequent work designing and characterizing EphA4 targeting agents identified a compound (123C4) that prolonged survival in SOD1 G93A mice 7 . However, that compound was found to act as an EphA4 agonist in cellular assays, raising questions about whether the in vivo benefits were due to EphA4 activation or EphA4 down-regulation following agonist binding.…”

Section: Introductionmentioning

confidence: 99%

Inducible EphA4 knockout causes motor deficits in young mice and is not protective in the SOD1G93A mouse model of ALS

Domínguez¹,

Earr²,

Dourado³

et al. 2020

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss that ultimately leads to fatal paralysis. Reducing levels or function of the tyrosine kinase, ephrin type-A receptor 4 (EphA4), has been suggested as a potential approach for slowing disease progression in ALS. Because EphA4 plays roles in embryonic nervous system development, study of constitutive knockout (KO) of EphA4 in mice is limited due to confounding phenotypes with homozygous knockout. We used a tamoxifen-inducible EphA4 conditional KO mouse to achieve strong reduction of EphA4 levels in postnatal mice to test for protective effects in the SOD1G93A model of ALS. We found that EphA4 KO in young mice, but not older adult mice, causes defects in muscle function, consistent with a prolonged postnatal role for EphA4 in adolescent muscle growth. When testing the effects of inducible EphA4 KO at different timepoints in SOD1G93A mice, we found no benefits on motor function or disease pathology, including muscle denervation and motor neuron loss. Our results demonstrate deleterious effects of reducing EphA4 levels in juvenile mice and do not provide support for the hypothesis that widespread EphA4 reduction is beneficial in the SOD1G93A mouse model of ALS.

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Potent and Selective EphA4 Agonists for the Treatment of ALS

Cited by 47 publications

References 43 publications

Reducing EphA4 before disease onset does not affect survival in a mouse model of Amyotrophic Lateral Sclerosis

Reducing EphA4 before disease onset does not affect survival in a mouse model of Amyotrophic Lateral Sclerosis

Reduction of ephrin-A5 aggravates disease progression in amyotrophic lateral sclerosis

Inducible EphA4 knockout causes motor deficits in young mice and is not protective in the SOD1G93A mouse model of ALS

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