The extracellular matrix glycoprotein tenascin-C is beneficial for spinal cord regeneration.
Chen Jian,Joon Lee Hyun,Jakovcevski Igor,Shah Ronak,Bhagat Neha,Loers Gabriele,Liu Hsing-Yin,Meiners Sally,Taschenberger Grit,Kügler Sebastian,Irintchev Andrey,Schachner Melitta
Molecular therapy : the journal of the American Society of Gene Therapy
Tenascin-C (TNC), a major component of the extracellular matrix, is strongly upregulated after injuries of the central nervous system (CNS) but its role in tissue repair is not understood. Both regeneration promoting and inhibiting roles of TNC have been proposed considering its abilities to both support and restrict neurite outgrowth in vitro. Here, we show that spontaneous recovery of locomotor functions after spinal cord injury is impaired in adult TNC-deficient (TNC(-/-)) mice in comparison to wild-type (TNC(+/+)) mice. The impaired recovery was associated with attenuated excitability of the plantar Hoffmann reflex (H-reflex), reduced glutamatergic input, reduced sprouting of monaminergic axons in the lumbar spinal cord and enhanced post-traumatic degeneration of corticospinal axons. The degeneration of corticospinal axons in TNC(-/-) mice was normalized to TNC(+/+) levels by application of the alternatively spliced TNC fibronectin type III homologous domain D (fnD). Finally, overexpression of TNC-fnD via adeno-associated virus in wild-type mice improved locomotor recovery, increased monaminergic axons sprouting, and reduced lesion scar volume after spinal cord injury. The functional efficacy of the viral-mediated TNC indicates a potentially useful approach for treatment of spinal cord injury.
Non-viral gene therapy for spinal cord regeneration.
Yao Li,Yao Sheng,Daly William,Hendry William,Windebank Anthony,Pandit Abhay
Drug discovery today
Spinal cord injury (SCI) normally results in life-long disabilities and a broad range of secondary complications. Advances in therapeutic delivery during the past few decades offer hope for such victims. However, the limited functional improvement shown in in vivo studies hinders effective therapeutic application in clinical practice. Recent studies showed that gene vectors can transfect cells present in the lesion of an injured spinal cord (endogenous cells) and thereby produce therapeutic molecules with long-lasting biological effects that promote neural tissue regeneration. In this article we review recent advances in non-viral gene delivery into neural cells and their use for gene therapy in SCI.
The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127.
Wu Hong-Fu,Cen Jing-Sheng,Zhong Qian,Chen Luming,Wang Jue,Deng David Y B,Wan Yong
Lingo-1 is selectively expressed on both oligodendrocytes and neurons in the central nervous system (CNS) and serves as a key negative regulator of nerve regeneration, implying a therapeutic target for spinal cord injury (SCI). Here we described a strategy to knock-down Lingo-1 expression in vivo using lentiviral vectors encoding Lingo-1 short harpin interfering RNA (shRNA) delivered by Pluronic F-127 (PF-127) gel, a non-cytotoxic scaffold and gene delivery carrier, after the complete transection of the T10 spinal cord in adult rats. We showed administration of PF-127 encapsulating Lingo-1 shRNA lentiviral vectors efficiently down-regulated the expression of Lingo-1, and exhibited transduction efﬁciency comparable to using vectors alone in oligodendrocyte culture in vitro. Furthermore, similar silencing effects and higher transfection efficiency were observed in vivo when Lingo-1 shRNA was co-delivered to the injured site by PF-127 gel with lower viral concentrations. Cografting of gel and Lingo-1 RNAi significantly promoted functional recovery and nerve regeneration, enhanced neurite outgrowth and synapses formation, preserved myelinated axons, and induced the proliferation of glial cells. In addition, the combined implantation also improved neuronal survival and inhibited cell apoptosis, which may be associated with the attenuation of endoplasmic reticulum (ER) stress after SCI. Together, our data indicated that delivering Lingo-1 shRNA by gel scaffold was a valuable treatment approach to SCI and PF-127 delivery of viral vectors to the spinal cord may provide strategy to study and develop therapies for SCI.