Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries

• Published in: Journal of controlled release Vol. 204; pp. 1 - 10
• Main Authors: Thomas, Aline M., Palma, Jaime L., Shea, Lonnie D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.04.2015
• Subjects: Acute Disease; Animals; Astrocytes - cytology; Astrocytes - metabolism; Chronic Disease; Gelatin Sponge, Absorbable - chemistry; Gene delivery; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors; Hedgehog Proteins - genetics; HEK293 Cells; Humans; Hydrogels - chemistry; Injections, Spinal; Intrathecal delivery; Lentivirus; Lentivirus - genetics; Luciferases - genetics; Macro-porous sponge; Mice; Oligodendroglia - cytology; Oligodendroglia - metabolism; Polyethylene Glycols - chemistry; Porosity; Spinal Cord - metabolism; Spinal Cord - pathology; Spinal Cord Injuries - genetics; Spinal Cord Injuries - pathology; Spinal Cord Injuries - therapy; Spinal cord injury; Spinal Cord Regeneration - genetics; Transfection; Intrathecal delivery; Gene delivery; Macro-porous sponge; Spinal cord injury; Lentivirus
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2015.02.032

The environment within the spinal cord after injury, which changes in the progression from the acute to chronic stages, limits the extent of regeneration. The delivery of inductive factors to promote regeneration following spinal cord injury has been promising, yet, few strategies are versatile to allow delivery during acute or chronic injury that would facilitate screening of candidate therapies. This report investigates the intrathecal delivery of lentiviruses for long-term expression of regenerative factors. Lentivirus-filled sponges were inserted into the intrathecal space surrounding the spinal cord, with transgene expression observed within multiple cell types that persists for 12weeks for both intact and injured spinal cord, without any apparent damage to the spinal cord tissue. Sponges loaded with lentivirus encoding for Sonic hedgehog (Shh) were investigated for acute (delivered at 0weeks) and chronic (at 4weeks) injuries, and for multiple locations relative to the injury. In an acute model, sponges placed directly above the injury increased oligodendrocyte and decreased astrocyte presence. Sponges placed caudal to the injury had reduced impact on oligodendrocytes and astrocytes in the injury. In a chronic model, sponges increased oligodendrocyte and decreased astrocyte presence. Furthermore, the effect of Shh was shown to be mediated in part by reduction of Bmp signaling, monitored with an Msx2-sensitive reporter vector. The implantation of lentivirus-loaded biomaterials intrathecally provides the opportunity to induce the expression of a factor at a specified time without entering the spinal cord, and has the potential to promote gene delivery within the spinal cord, which can influence the extent of regeneration. [Display omitted]