LIF (AM424), a promising growth factor for the treatment of ALS.
Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998.
Kurek
J B
JB
AMRAD Corporation Ltd, Melbourne, Australia. jkurek@amrad.com.au
Radford
A J
AJ
Crump
D E
DE
Bower
J J
JJ
Feeney
S J
SJ
Austin
L
L
Byrne
E
E
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006131:Growth Inhibitors / Q000737:chemistry / Q000502:physiology / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000737:chemistry / Q000502:physiology / Q000627:therapeutic use*; D051379:Mice; D008818:Mice, Neurologic Mutants; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009420:Nervous System / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018121:Receptors, Cytokine / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D018121:Receptors, Cytokine; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1