Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease resulting from motor neuron degeneration that causes muscle weakness, paralysis, and eventually respiratory failure. We investigated whether recombinant adeno-associated virus encoding human hepatocyte growth factor (rAAV-HGF) could generate beneficial effects in two mouse models with neuromuscular problems when intrathecally delivered to the subarachnoid space. We chose AAV serotype 1 (rAAV1) based on the expression levels and distribution of HGF protein in the lumbar spinal cord (LSC). After a single intrathecal (IT) injection of rAAV1-HGF, the protein level of HGF in the LSC peaked on day 14 and thereafter gradually decreased over the next 14 weeks. rAAV1-HGF was initially tested in the mouse nerve crush model. IT injection of rAAV1-HGF improved mouse hindlimb strength and rotarod performance, while histological analyses showed that the length of regenerated axons was increased and the structure of the neuromuscular junction (NMJ) was restored. rAAV1-HGF was also evaluated in the SOD1-G93A transgenic (TG) mouse model. Again, rAAV1-HGF not only improved motor performance but also increased the survival rate. Moreover, the number and diameter of spinal motor neurons (SMNs) were increased, and the shape of the NMJs restored. Data from in vitro motor cortical culture experiments indicated that treatment with recombinant HGF protein (rHGF) increased the axon length of corticospinal motor neurons (CSMNs). When cultures were treated with an ERK inhibitor, the effects of HGF on axon elongation, protein aggregation, and oxidative stress were suppressed, indicating that ERK phosphorylation played an important role(s). Taken together, our results suggested that HGF might play an important role(s) in delaying disease progression in the SOD1-G93A TG mouse model by reducing oxidative stress through the control of ERK phosphorylation.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, in which the motor neurons of the central nervous system degenerate progressively [13, 23, 49]
Construction of rAAV vectors expressing human Hepatocyte growth factor (HGF) In this study, we tested whether an HGF-expressing rAAV vector could facilitate the regeneration of motor neurons and alleviate disease progression of ALS when delivered to the subarachnoid space through IT injection
Values are represented as mean ± standard error mean (SEM)
Summary
ALS is a neurodegenerative disease, in which the motor neurons of the central nervous system degenerate progressively [13, 23, 49]. A variety of chemicals, recombinant proteins, and gene therapies have been explored to develop treatment methods for ALS, but to date, only two small molecules, riluzole and edaravone, have been approved by the FDA [3, 5, 39]. Their therapeutic effects are relatively low: riluzole delays the time to tracheostomy by 2 to 3 months, and edaravone improves the ALSFRS-R score by 33%. In the SOD1-G93A TG mouse model, disease progression has been delayed when HGF or Met expression was introduced by generating double TG mice, or when rHGF was intrathecally delivered, indicating that HGF might play an important role(s) in ALS [10, 16, 48]
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