Non-viral gene therapy for spinal cord regeneration

Abstract

Spinal cord injury 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 spinal cord injury.

Intrathecal injection of a therapeutic gene-containing polyplex to treat spinal cord injury

“…On the other hand, other non-viral systems, especially lipidbased systems, generally have disadvantages in low efficiency of in vivo gene introduction compared with the remarkably high capacity for cultured cells in some cases, comparable to capacities of viral vectors [48,49]. Indeed, for SCI, there are few reports in animal studies showing sufficient improvement of neural function by introduction of therapeutic molecules, although a considerable number of systems achieved in vitro transgene expression in neural cells such as neurons and astrocytes [50].…”

Gene Delivery Strategies to Promote Spinal Cord Repair

“…Compared to their viral counterparts, nonviral gene delivery methods are significantly less efficient; however, many researchers have focused on improving vector stability and cell internalization of delivered genes. 123 , 124 As with viral vectors, designing strategies to avoid detection by the immune system has also been a major goal. Generally, nonviral delivery strategies seek to complex nucleic acids with various polymers, biomolecules, nanoparticles, lipid vesicles, and other materials that serve to protect naked plasmid and carry it across cell membranes so the nucleic acid payload is released in the cytosol ( Fig.…”

“… 127 Despite many improvements to vectors over calcium phosphate nanoparticles, nonviral delivery to the CNS, and in particular the injured spinal cord, has been more difficult than delivery to peripheral tissues due to inefficient crossing of the blood–brain barrier and vector instability when exposed to the highly inflammatory environment present after injury. For comprehensive reviews of nonviral gene delivery in the CNS, refer to reviews by Yao et al 123 and Pérez-Martínez et al 125 …”

Non-Viral Nanosystems for Gene and Small Interfering RNA Delivery to the Central Nervous System: Formulating the Solution

“…Indeed, direct administration to the CSF by intrathecal injection or infusion effectively bypasses the BBB and can facilitate delivery of nucleic acids to CNS tissues . This approach offers great potential for local expression or silencing of target genes in certain conditions, such as spinal cord injury or pain . However, nucleic acids delivered to the CSF still encounter obstacles which limit their effectiveness, including rapid clearance from the CSF, the blood–CSF barrier (BCSFB) and limited diffusion from the CSF into the brain parenchyma .…”

“…110 This approach offers great potential for local expression or silencing of target genes in certain conditions, such as spinal cord injury or pain. 48,111,112 However, nucleic acids delivered to the CSF still encounter obstacles which limit their effectiveness, including rapid clearance from the CSF, the blood-CSF barrier (BCSFB) and limited diffusion from the CSF into the brain parenchyma. 110 The BCSFB consists of epithelial cells joined by tight junctions and acts as the interface between the blood and the CNS.…”