K Li, C Nicaise, D Sannie, TJ Hala, E Javed, JL Parker, R Putatunda, KA Regan, V Suain, JP Brion, F Rhoderick, MC Wright, DJ Poulsen, AC Lepore. Overexpression of the astrocyte glutamate transporter, GLT1, exacerbates phrenic motor neuron degeneration, diaphragm compromise and forelimb motor dysfunction following cervical contusion spinal cord injury. The Journal of Neuroscience. 34 (22):7622-38, 2014.

We found that function of the astrocyte glutamate transporter, GLT1, is significantly compromised after cervical SCI. Specifically, we demonstrated persistent loss of expression, as well as reduced functional glutamate uptake, in regions of respiratory neural circuit degeneration. Furthermore, we demonstrated that overexpressing GLT1 selectively in astrocytes of the injured spinal cord (using an anatomically-targeted AAV delivery-based approach) alters secondary injury processes and consequent functional outcomes after SCI.

K Li, E Javed, TJ Hala, D Sannie, KA Regan, NJ Maragakis, MC Wright, DJ Poulsen, AC Lepore. Transplantation of glial progenitors that overexpress glutamate transporter GLT1 preserves diaphragm function following cervical SCI. Molecular Therapy. 23 (3): 533-48, 2015.

Stem/progenitor cell transplantation-based replacement of astrocytes is a novel and potentially powerful therapeutic strategy for treating CNS diseases such as SCI. Towards this goal (and as a novel strategy to restore function of the astrocyte glutamate transporter GLT1), we transplanted astrocyte progenitors – including those engineered to overexpress GLT1 – into a rodent model of cervical contusion SCI. We found that intraspinal transplantation of GLT1-overexpressing astrocyte progenitors resulted in significant protection of respiratory neural circuitry and preservation of diaphragm innervation and function. In a follow-up publication (Li et al., Experimental Neurology, 2015), we derived induced Pluripotent Stem (iPS) cells from human donors, efficiently differentiated them along the astrocyte lineage, and demonstrated their therapeutic efficacy with respect to respiratory neural circuit protection and preservation of diaphragm function when transplanted into the injured cervical spinal cord.

A Falnikar, TJ Hala, DJ Poulsen, AC Lepore. GLT1 overexpression reverses established thermal hyperalgesia and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury. GLIA, 64 (3): 396-406, 2016.

As loss of function of the astrocyte glutamate transporter GLT1 in spinal cord dorsal horn contributes to the hyperexcitability of pain transmission neurons that underlies persistent neuropathic pain following SCI, we used an AAV8-GLT1 vector to restore GLT1 expression selectively in superficial dorsal horn astrocytes. In the mouse model of cervical contusion SCI, we found that intraspinal delivery of AAV8-GLT1 excitingly was able to reverse already-established neuropathic pain behavior and over-activation of superficial dorsal horn pain neurons.

B Ghosh *, Z Wang *, J Nong, MW Urban, VA Trovillion, MC Wright, Y Zhong, AC Lepore. Local delivery to the injured cervical spinal cord using an engineered hydrogel preserves diaphragmatic respiratory function. The Journal of Neuroscience. * Co-first authors. 38 (26): 5982-5995, 2018.

We developed an innovative biomaterial-based approach to repair the critical neural circuitry that controls diaphragm activation by locally delivering brain-derived neurotrophic factor (BDNF) to injured cervical spinal cord. Specifically, we developed a novel hydrogel-based system loaded with polysaccharide-BDNF particles self-assembled by electrostatic interactions that can be safely implanted in the intrathecal space for achieving local BDNF delivery with controlled dosing and duration. Our findings demonstrate that local BDNF hydrogel delivery is a robustly-effective and safe strategy to restore diaphragm function after SCI. In addition, we demonstrated novel therapeutic mechanisms by which BDNF can repair respiratory neural circuitry.

MW Urban *, B Ghosh *, CG Block, M Goulão, GM Smith, MC Wright, S Li, AC Lepore. Long-distance axon regeneration promotes recovery of diaphragmatic respiratory function after spinal cord injury. eNeuro. 6 (5), 2019. * Co-first authors.

In a rat model of cervical SCI, we demonstrated that systemic administration of a PTEN antagonist peptide robustly restores diaphragmatic respiratory function and promotes substantial, long-distance regeneration of injured respiratory rVRG axons through the lesion and back into the intact caudal spinal cord where these regrowing rVRG axons form large numbers of excitatory synaptic connections with their phrenic motor neuron (PhMN) targets, demonstrating effective restoration of rVRG-PhMN-diaphragm circuitry.