Injection of a soluble fragment of neural agrin (NT-1654) considerably improves the muscle pathology caused by the disassembly of the neuromuscular junction

Stefan Hettwer; Shuo Lin; Stefan Kucsera; Monika Haubitz; Filippo Oliveri; Ruggero G Fariello; Markus A Ruegg; Jan W Vrijbloed

doi:10.1371/journal.pone.0088739

Injection of a soluble fragment of neural agrin (NT-1654) considerably improves the muscle pathology caused by the disassembly of the neuromuscular junction

PLoS One. 2014 Feb 10;9(2):e88739. doi: 10.1371/journal.pone.0088739. eCollection 2014.

Authors

Stefan Hettwer¹, Shuo Lin², Stefan Kucsera¹, Monika Haubitz¹, Filippo Oliveri², Ruggero G Fariello¹, Markus A Ruegg², Jan W Vrijbloed¹

Affiliations

¹ Neurotune AG, Schlieren, Zurich, Switzerland.
² Biozentrum, University of Basel, Basel, Switzerland.

Abstract

Treatment of neuromuscular diseases is still an unsolved problem. Evidence over the last years strongly indicates the involvement of malformation and dysfunction of neuromuscular junctions in the development of such medical conditions. Stabilization of NMJs thus seems to be a promising approach to attenuate the disease progression of muscle wasting diseases. An important pathway for the formation and maintenance of NMJs is the agrin/Lrp4/MuSK pathway. Here we demonstrate that the agrin biologic NT-1654 is capable of activating the agrin/Lrp4/MuSK system in vivo, leading to an almost full reversal of the sarcopenia-like phenotype in neurotrypsin-overexpressing (SARCO) mice. We also show that injection of NT-1654 accelerates muscle re-innervation after nerve crush. This report demonstrates that a systemically administered agrin fragment has the potential to counteract the symptoms of neuromuscular disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agrin / administration & dosage*
Agrin / pharmacology*
Animals
Body Weight / drug effects
HEK293 Cells
Humans
Injections
Mice
Mice, Inbred C57BL
Muscle Fibers, Skeletal / drug effects
Muscle Fibers, Skeletal / pathology
Muscle Strength / drug effects
Muscle, Skeletal / drug effects
Muscle, Skeletal / pathology*
Muscle, Skeletal / physiopathology
Nerve Crush
Neuromuscular Junction / drug effects
Neuromuscular Junction / metabolism
Neuromuscular Junction / pathology*
Phenotype
Receptors, Cholinergic / metabolism
Sarcopenia / complications
Sarcopenia / pathology
Sarcopenia / physiopathology
Sciatic Nerve / drug effects
Sciatic Nerve / metabolism
Sciatic Nerve / pathology
Serine Endopeptidases / metabolism
Solubility

Substances

Agrin
Receptors, Cholinergic
Serine Endopeptidases
neurotrypsin

Grants and funding

This work was supported by the Swiss Commission for Technology and Innovation (CTI), project number 12887.1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.