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A natural human IgM that binds to gangliosides is therapeutic in murine models of
amyotrophic lateral sclerosis
#MMPMID26035393
Xu X
; Denic A
; Jordan LR
; Wittenberg NJ
; Warrington AE
; Wootla B
; Papke LM
; Zoecklein LJ
; Yoo D
; Shaver J
; Oh SH
; Pease LR
; Rodriguez M
Dis Model Mech
2015[Aug]; 8
(8
): 831-42
PMID26035393
show ga
Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurological disease
that primarily affects spinal cord anterior horn cells and their axons for which
there is no treatment. Here we report the use of a recombinant natural human IgM
that binds to the surface of neurons and supports neurite extension, rHIgM12, as
a therapeutic strategy in murine models of human ALS. A single 200?µg
intraperitoneal dose of rHIgM12 increases survival in two independent
genetic-based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10?days,
delays the onset of neurological deficits by 16?days, delays the onset of weight
loss by 5?days, and preserves spinal cord axons and anterior horn neurons.
Immuno-overlay of thin layer chromatography and surface plasmon resonance show
that rHIgM12 binds with high affinity to the complex gangliosides GD1a and GT1b.
Addition of rHIgM12 to neurons in culture increases ?-tubulin tyrosination
levels, suggesting an alteration of microtubule dynamics. We previously reported
that a single peripheral dose of rHIgM12 preserved neurological function in a
murine model of demyelination with axon loss. Because rHIgM12 improves three
different models of neurological disease, we propose that the IgM might act late
in the cascade of neuronal stress and/or death by a broad mechanism.
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