Sustained delivery of IL10 and SHH to promote spinal cord regeneration after injury
Hal X. Nguyen2, Elizabeth S. Fisher1, Usha Nekanti2, Rebecca A. Nishi2, Steven Lotz1, Natasha A. Lowry1, Aileen J. Anderson2, Sally Temple1.
1Neural Stem Cell Institute, Rensselaer NY, 12144; 2University of California Irvine, Irvine CA, 92697
Spinal cord injury (SCI) can result in paralysis for which treatment options are limited. Damage and cell death from the injury promote pro-inflammatory responses such as immune cell activation and recruitment, further enhancing inflammation. However, SCI also induces beneficial anti-inflammatory responses, complicating the search for effective therapies. Therefore, modulating the microenvironment may provide an avenue to reduce inflammation and promote regeneration in the injured cord.
Poly(lactic-co-glycolic acid) (PLGA)-based biodegradable beads that release factors locally offer a clinically compatible method to manipulate the microenvironment while providing long-term modulation and avoiding the side effects of systemic administration. Our lab previously showed that acute, prolonged sonic hedgehog (SHH) exposure in the spinal cord via locally delivered biodegradable PLGA microbeads increases axon sprouting and sparing, reduces scar formation, and improves functional recovery in mice in two SCI models. Since SHH is a growth factor which assists in SCI regeneration, we also targeted the immediate inflammatory environment to reduce the initial damage caused by infiltrating immune cells. Interleukin-10 (IL10) is an anti-inflammatory cytokine shown to have neuroprotective effects following SCI, reducing pain and promoting functional recovery.
Our current work tests the individual effects of SHH beads and IL10 plasmid DNA (IL10pDNA) beads on the inflammatory environment and functional recovery in Long Evans rats after acute and chronic SCI. In vitro, IL10pDNA beads are taken up by macrophages and alter macrophage phenotype.
Preliminary behavioral test results indicate that IL10pbead administration provides functional recovery in the acute, but not chronic phase of injury, while SHH is beneficial in the chronic, but not acute phase. Studies examining the lesion volume and cellular responses to treatment using stereological analysis are on-going. Future work will combine IL10pDNA and SHH beads in rats to determine the combinatorial effect of our treatments.
Funded by NY SCIRB C30605GG (AJA, ST) and Foundation to Cure Paralysis.