Intrathecal Delivery of Hepatocyte Growth Factor From Amyotrophic Lateral Sclerosis Onset Suppresses Disease Progression in Rat Amyotrophic Lateral Sclerosis Model

• Published in: Journal of neuropathology and experimental neurology Vol. 66; no. 11; pp. 1037 - 1044
• Main Authors: Ishigaki, Aya, Aoki, Masashi, Nagai, Makiko, Warita, Hitoshi, Kato, Shinsuke, Kato, Masako, Nakamura, Toshikazu, Funakoshi, Hiroshi, Itoyama, Yasuto
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.11.2007; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Animals, Genetically Modified; Biological and medical sciences; Blotting, Western; Caspases - drug effects; Caspases - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Disease Progression; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Transporter 2 - drug effects; Excitatory Amino Acid Transporter 2 - metabolism; Hepatocyte Growth Factor - administration & dosage; Humans; Immunohistochemistry; Infusion Pumps, Implantable; Injections, Spinal; Medical sciences; Motor Neurons - drug effects; Nerve Degeneration - drug therapy; Neurology; Proto-Oncogene Proteins c-met - metabolism; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - pathology; Vascular diseases and vascular malformations of the nervous system; X-Linked Inhibitor of Apoptosis Protein - drug effects; X-Linked Inhibitor of Apoptosis Protein - metabolism; Animal model; Nervous system diseases; Rat; Enzyme; Hepatocyte growth factor; Rodentia; Transgenic animal; Amyotrophic lateral sclerosis; Superoxide dismutase; Superoxide dismutase-1 (SOD1); Transgenic rat; Continuous intrathecal delivery; Vertebrata; Mammalia; Neurodegeneration; Central nervous system disease; Degenerative disease; Oxidoreductases; Spinal cord disease; Intrathecal
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/nen.0b013e318159886b

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 μg and 200 μg 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.