FGF22 gene therapy as a new “synaptogenic” treatment strategy for spinal cord injury
Funded in: 2016, 2017, 2018
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Problem: After SCI, the remodeling of axonal circuits is limited resulting in attenuated functional recovery.
Target: FGF22 as presynaptic organizer is required for efficient endogenous axonal and synaptic remodeling.
Goal: To explore therapeutic effects of FGF22 gene in improving circuit remodeling.
The remodeling of axonal circuits is a major contributor to functional recovery following spinal cord injury. We have recently identified FGF22 - a presynaptic organizer - as a first mediator that is required for efficient endogenous axonal and synaptic remodeling after spinal cord injury (Jacobi et al., 201). FGF22 is a member of the FGF family and had been previously characterized as target derived presynaptic organizer in the developing nervous system (Umemori et al., 2004; Terauchi et al., 2010). We could now show that FGF22 and its receptors FGFR1 and FGFR2 are constitutively expressed in the adult nervous system and that genetic interference with FGF22 signaling either on the level of the ligand or its receptors limits the formation and maturation of new synapses in the injured spinal cord. This perturbation then results in deficient detour circuit formation and attenuated functional recovery (Jacobi et al., 2015).
While we thus know that endogenous FGF22 is necessary for efficient detour circuit formation following spinal cord injury, it is currently unclear, whether such synaptogenic mediators can be exploited therapeutically to enhance synapse formation, axonal remodeling and functional recovery after injury. In this project I now want to explore this option and determine whether FGF22 gene therapy can trigger synapse formation and maturation and thereby improve circuit remodeling in spinal cord-injured animals (Goal 1), evaluate synergistic effects of enhanced FGF22 signaling and concomitant induction of axon collateral formation on the remodeling process (using combined FGF22 and STAT3 gene therapy) (Goal 2) and determine the therapeutic effects of these strategies on the behavioral and electrophysiological recovery of the animals (Goal 3).