Regenerative medicine approaches to protecting and repairing the retina and the optic nerve.
The failure of central nervous system (CNS) neurons to regenerate after injury or disease remains a persistent clinical problem. In the visual system, this failure leads to axon degeneration, retinal ganglion cell death, and irreversible vision loss. The goals of the Steketee lab include developing clinically relevant therapies to promote functional repair in the retina and in the optic nerve after injury or disease by applying regenerative medicine strategies to alter the default healing response in the CNS, scarring, to promote functional tissue remodeling. To achieve our goals we are using two complimentary approaches: extracellular matrix (ECM) technology and nanotechnology to modulate mitochondrial function. First, ECM technology is a translational, regenerative medicine strategy that uses ECM bioscaffolds derived from decellularizing specific tissues or organs to promote functional tissue remodeling in tissues the body is unable to repair by default. Over 4 million patients have been treated with over 60 FDA approved ECM-based products used to promote pro-repair tissue remodeling in numerous tissues, including skin, heart, esophagus, bladder, muscle, and bone among others. Though the mechanisms are not fully understood, ECM bioscaffolds appear to fundamentally change the healing response by providing signals to the host immune system that stimulate an inductive wound healing response to promote site-specific tissue remodeling. We are now applying ECM technology to repair the CNS, specifically the retina and the optic nerve. Second, we are developing nanoparticles to deliver drugs specifically to the mitochondria in retinal ganglion cell axons. These drugs are designed to modulate the function of the mitochondrial electron transport chain to minimize oxidative phosphorylation during times of injury or stress. This strategy is designed to minimize oxidative cellular damage due to unregulated reactive oxygen species production after injury and to force the cell to rely more on glycolysis for energy since glycolytic metabolites support regeneration. In collaboration with a number of labs in the McGowan Institute, we are currently working toward combining ECM technology with targeted nanotherapeutics into injectable hydrogels and biohybrid ECM/polymer sheets that can used to treat a variety of injuries to the retina or to the optic nerve.
Lathrop, K. and Steketee, M.B. Mitochondrial dynamics in retinal ganglion cell axon regeneration and growth cone guidance. Peer Reviewed Review, Journal of Ocular Biology, 2013.
Steketee, M.B. and Goldberg, J.L. Signaling endosomes and growth cone motility in axon regeneration. Axon Growth and Regeneration. International review of Neurobiology, 2012.
Steketee, M.B., Moysidis, S., Kreymerman, A., Silva, J., Weinstein, J.E., Iqbal S., Goldberg, J.L. Mitochondrial dynamics regulate growth cone motility, guidance, and neurite growth rate in retinal ganglion cells. IOVS 12: 10298, 2012.
Steketee, M.B., Moysidis, S.N., Weinstein, J.W., Pita-Thomas, W, Xiao-Lu Jin, Raju, H.B., Iqbal, S., Goldberg, J.L. Signaling endosome localization regulates growth cone dynamics and neurite growth, PNAS 108 (47) 19042-19047, 2011.