Antisense-mediated reduction of EphA4 in the adult CNS does not improve the function of mice with amyotrophic lateral sclerosis

NEUROBIOLOGY OF DISEASE

卷:114

Article

Ling, Karen K.¹  Jackson, Michaela¹  Alkam, Duah²  Liu, Dawei⁶  Allaire, Norm⁶  Sun, Chao⁶  Kiaei, Mahmoud^2,3,4,5  McCampbell, Alexander⁶  Rigo, Frank¹ 

[1] Ionis Pharmaceut, Carlsbad, CA USA

[2] Univ Arkansas Med Sci, Dept Neurol, Little Rock, AR 72205 USA

[3] Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA

[4] Univ Arkansas Med Sci, Ctr Translat Neurosci, Little Rock, AR 72205 USA

[5] Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA

[6] Biogen Inc, 14 Cambridge Ctr, Cambridge, MA 02142 USA

关键词: Amyotrophic lateral sclerosis;    Ephrin receptor A4;    Antisense oligonucleotides;    Superoxide dismutase 1;    Profilin 1;   

DOI  :  10.1016/j.nbd.2018.03.002

来源: Elsevier

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is a fatal adult onset motor neuron disease characterized by progressive denervation and subsequent motor impairment. EphA4, a negative regulator of axonal growth, was recently identified as a genetic modifier in fish and rodent models of ALS. To evaluate the therapeutic potential of EphA4 for ALS, we examined the effect of CNS-directed EphA4 reduction in preclinical mouse models of ALS, and assessed if the levels of EPHA4 mRNA in blood correlate with disease onset and progression in human ALS patients. We developed antisense oligonucleotides (ASOs) to specifically reduce the expression of EphA4 in the central nervous system (CNS) of adult mice. Intracerebroventricular administration of an Epha4-ASO in wild type mice inhibited Epha4 mRNA and protein in the brain and spinal cord, and promoted re-innervation and functional recovery after sciatic nerve crush. In contrast, lowering of EphA4 in the CNS of two mouse models of ALS (SOD1(G93A) and PFN1(G118v)) did not improve their motor function or survival. Furthermore, the level of EPHA4 mRNA in human blood correlated weakly with age of disease onset, and it was not a significant predictor of disease progression as measured by ALS Functional Rating Scores (ALSFRS). Our data demonstrates that lowering EphA4 in the adult CNS may not be a stand-alone viable strategy for treating ALS.

【 授权许可】

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