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.