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 inc ludes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signa l 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. It s effects in muscle also include stimulating myoblast proliferation in vitr o, and up-regulation after muscle injury. LIF will also stimulate muscle re generation in vivo when applied exogenously after injury. In published stud ies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 mu g/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF i s expressed in low levels by spinal cord neurones with significant up-regul ation 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 toget her, the data suggests LIF is a physiologically relevant trophic factor wit h implications in clinical medicine as a therapy for ALS, and a human recom binant form (AM424), entered human clinical trials during 1998. (C) 1998 El sevier Science B.V, Ail rights reserved.