Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model.
Hepatocyte growth factor (HGF) is one of the most potent survival-promoting factors for motor neurons. We showed that introduction of the HGF gene into neurons of G93A transgenic mice attenuates motor neuron degeneration and increases the lifespan of these mice. Currently, treatment regimens using recombinant protein are closer to clinical application than gene therapy. To examine its protective effect on motor neurons and therapeutic potential we administered human recombinant HGF (hrHGF) by continuous intrathecal delivery to G93A transgenic rats at doses of 40 or 200 microg and 200 microg at 100 days of age (the age at which pathologic changes of the spinal cord appear, but animals show no clinical weakness) and at 115 days (onset of paralysis), respectively, for 4 weeks each. Intrathecal administration of hrHGF attenuates motor neuron degeneration and prolonged the duration of the disease by 63%, even with administration from the onset of paralysis. Our results indicated the therapeutic efficacy of continuous intrathecal administration of hrHGF in transgenic rats and should lead to the consideration for further clinical trials in amyotrophic lateral sclerosis using continuous intrathecal administration of hrHGF.
Ishigaki
Aya
A
Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Aoki
Masashi
M
Nagai
Makiko
M
Warita
Hitoshi
H
Kato
Shinsuke
S
Kato
Masako
M
Nakamura
Toshikazu
T
Funakoshi
Hiroshi
H
Itoyama
Yasuto
Y
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage*; D006801:Humans; D007150:Immunohistochemistry; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D009046:Motor Neurons / Q000187:drug effects*; D009410:Nerve Degeneration / Q000188:drug therapy*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects / Q000378:metabolism
D027342:Excitatory Amino Acid Transporter 2; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020169:Caspases