1. Leukaemia inhibitory factor (LIF) is a 180
amino acid single-chain
protein, named after its effect on haematopoietic cells. Leukaemia inhibitory factor belongs to a group of
cytokines that includes
ciliary neurotrophic factor,
interleukin (IL)-6,
IL-11, cardiotrophin-1 and
oncostatin M. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in
biological effect. 2. Research over the past 6-8 years has shown LIF to have potent neuromuscular activity. In vitro and in vivo studies on
axotomy and
nerve crush models demonstrate a powerful effect of LIF in enhancing the survival of both motor and sensory neurons, while reducing
denervation-induced
muscle atrophy. In models of both
axotomy induced neuronal death and in the wobbler mouse, LIF is active at doses as low as 1 microgram/kg delivered systemically. 3. In muscle, LIF will increase the rate of muscle regeneration in vivo when applied exogenously after injury and will stimulate intrinsic muscle repair following its targeted release to dystrophic muscle in the mdx mouse. Leukaemia inhibitory factor may also have a role as an adjunct to myoblast transfer
therapy, with studies showing that the
transplantation of genetically competent myoblasts into mdx mouse muscle is enhanced when cells are injected with LIF. 4. Distribution and pharmacokinetic studies have been conducted in primates with doses of 20 micrograms/kg recombinant human LIF given subcutaneously over 2 weeks tolerated without major side effects. 5. A
pharmaceutical form of recombinant human LIF (
AM424; AMRAD Operations, Richmond, Victoria, Australia) entered human clinical trials during 1997 and a phase I clinical trial in healthy volunteers has been completed. A phase I repeat dose study has also been completed in
cancer patients undergoing
chemotherapy. The primary indication for a phase II study is the treatment of
chemotherapy induced
peripheral neuropathy. Other potential indications include muscle
wasting diseases, acute nerve
trauma and
motor neuron disease. 6. The role of LIF in modulating nerve loss should make it an ideal candidate for the treatment of a number of neurological conditions. The phase I study represents the first trial in a programme for the clinical development of
AM424.