The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury

Abstract

Treatment options for chronic spinal cord injury (SCI) remain limited due to unfavourable changes in the microenvironment. Gene therapy can overcome these barriers through continuous delivery of therapeutic gene products to the target tissue. In particular, adeno-associated virus (AAV) vectors are potential candidates for use in chronic SCI, considering their safety and stable gene expression in vivo . Given that different AAV serotypes display different cellular tropisms, it is extremely important to select an optimal serotype for establishing a gene transfer system during the chronic phase of SCI. Therefore, we generated multiple AAV serotypes expressing ff Luc-cp156, a fusion protein of firefly luciferase and Venus, a variant of yellow fluorescent protein with fast and efficient maturation, as a reporter, and we performed intraparenchymal injection in a chronic SCI mouse model. Among the various serotypes tested, AAVrh10 displayed the highest photon count on bioluminescence imaging. Immunohistological analysis revealed that AAVrh10 showed favourable tropism for neurons, astrocytes, and oligodendrocytes. Additionally, with AAVrh10, the area expressing Venus was larger in the injury epicentre and extended to the surrounding tissue. Furthermore, the fluorescence intensity was significantly higher with AAVrh10 than with the other vectors. These results indicate that AAVrh10 may be an appropriate serotype for gene delivery to the chronically injured spinal cord. This promising tool may be applied for research and development related to the treatment of chronic SCI.

The use of viral vectors to promote repair after spinal cord injury

“…As research on gene therapy continues, new serotypes will be discovered or developed to manipulate gene expression more efficiently and/or specifically. For instance, a recently generated serotype AAVrh10 more effectively transduces neurons, oligodendrocytes, and astrocytes in a chronic SCI model when compared to AAV5 and -6 ( Hoshino et al, 2019 ).…”

Future Prospects of Gene Therapy for Friedreich’s Ataxia

“…For the treatment of FA, both serotypes are extremely promising given their tropism towards the cerebellum, spinal cord, and heart. CNS, Skeletal muscle, Heart [64,65] As previously stated, the two major drawbacks of viral vectors are the mutational risk by insertion of the vector genome in the genomic DNA (genotoxicity) and the immune response that they may cause (immunotoxicity). Genotoxicity can be easily avoided by using non-integrative vectors such as AAV or HSV.…”

Stem Cell Secretome for Spinal Cord Repair: Is It More than Just a Random Baseline Set of Factors?

“…Adeno-associated virus (AVV) vectors have been successfully translated to the clinic for conditions such as inherited retinal disorders or haemophilia B [145]. The AVV vector is a very effective gene transfer system for delivering therapeutic gene products to the injured spinal cord [146]. In other studies, lentiviruses have been used as polycistronic vectors to deliver the genes of multiple therapeutic proteins [147], thus enhancing axonal growth and increasing functional recovery after spinal cord injury.…”