Characterization of macrophage migration inhibitory factor as a therapeutic target for amyotrophic lateral sclerosis

Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the loss of upper and lower motor neurons. Transgenic mice expressing mutant SOD1 develop paralysis and accumulate misfolded SOD1 (mSOD1). We have shown that macrophage migration inhibitory factor (MIF) is able to directly inhibit mutant SOD1 misfolding. Furtheremore, complete elimination of endogenous MIF accelerates disease onset and late disease progression and shortens the lifespan of mutant SOD1 mice with higher amounts of mSOD1 detected within the spinal cord.

Based on these findings, we used adeno associated viral (AAV) vectors to overexpress MIF in the spinal cord of mutant SOD1^G93A and loxSOD1^G37R mice. Mutant SOD1^G93A and loxSOD1^G37R mice injected with AAV2/9-MIF demonstrated a significant delay in disease onset and prolonged survival compared with their AAV2/9-GFP injected or non-injected littermates. Moreover, these mice accumulated reduced amounts of mSOD1 in their spinal cords.

Of more therapeutic relevance, would be to inject MIF at the symptomatic stage of the disease, when disease diagnosis has been established. To this end, we utilize an AAV PHP.eB virus that has the ability to penetrate the blood-brain barrier (BBB), following peripheral injection at the symptomatic phase. We expect that injecting MIF at this stage, will delay disease progression and expand the lifespan of mutant SOD1 mice.

Our findings indicate that MIF acts as a chaperone for misfolded SOD1 in vivo and may have further implications regarding the therapeutic potential role of upregulation of MIF in modulating the specific accumulation of misfolded SOD1.