The concept for this special issue on “Viral Vectors for Gene Modification after Spinal Cord Injury” was initially proposed in 2019 at the last in person meeting of the Experimental Neurology Editorial Board before the COVID-19 pandemic, and was approved by the Editor-in-Chief with Elizabeth Bradbury, George Smith and Oswald Steward as Co-Guest Editors. The guest editors identified and contacted potential contributing authors, and the rate of acceptance of our invitations was unusually high, confirming that this was an opportune time for a special issue in this area. We are delighted in the way that the Special Issue has come together, and grateful for the enthusiastic participation of the contributors.
This Special Issue was designed to provide an overview of genetic engineering approaches to design and test therapeutic candidates for spinal cord injury (SCI) as well as to identify mechanisms and post-injury changes in spinal circuits after injury and/or recovery. Some articles in this issue review the literature and discuss the advantages and potential disadvantages of some of these approaches. The first article by Van Steenbergen and Bareyre provides a topical review on the use of chemogenetic approaches to functionally and anatomically dissect neural circuits within the spinal cord, while providing practical insights into advantages and general concerns using these designer compounds. The article by Sidney-Smith et al. discusses the use of peripherally delivered gene therapies as potential treatments for spinal cord disorders and viral modifications to increase the utility and function of this approach. In efforts to improve the safety of gene therapy approaches, De Winter et al. describe recent advances in the use of inducible viral vectors, which enable controlled expression of the therapeutic transgene. The design of a gene switch that evades immune cell detection ensures protection of the inducible gene therapy. An overview of anterograde and retrograde transsynaptic viral tracer approaches to map spinal cord circuits connecting onto peripheral targets is reviewed in the article by Fortino et al. They further discuss the utility of this approach to map the integration of transplanted neuronal precursor cells with host circuitry within the injured spinal cord. Viral systems have multiple advantages and several limitations in their ability to transfer genetic materials into neuronal and non-neuronal cells within the CNS. The paper by Islam and Tom highlights the advantages and use of various vector types, serotypes and promotors in targeting specific cell populations and the capacity and limitation of these viruses for therapeutic transgene expression.
Sherrington referred to motor neurons as the final common pathway, however, these motor neurons receive extensive innervation from the supraspinal regions that change after spinal cord injury or with functional recovery. Retrograde transportable adeno-associated viruses (AAVretro) are useful in identifying presynaptic supraspinal neuronal targets innervating specific regions of the spinal cord. Blackmore et al., discuss the use of AAVretro viral approaches to map and evaluate changes in the supraspinal connectome and the importance of these alterations in both the functional deficits after injury and recovery mediated by restorative therapies. This article also highlights the important perspective and priorities of those living with SCI and the importance of developing therapies to restore multiple functions that are lost, some of which are apparent only to those who are living with SCI. Likewise, the article by Metcalfe et al. examines differences in the supraspinal connectome dependent on regional locations within the spinal cord and the use of this method to simultaneously target multiple spinal pathways for gene therapy. Schrank and Satkunendrarajah provide a brief review of approaches using different types of retrogradely-transported vectors and clarify some seeming discrepancies between studies. This paper also highlights other strategies for multiple supraspinal pathway targeting, and highlight their potential uses in mapping, modulating and treating these neural networks.
To better understand the functional roles of specific neural circuits after SCI, several papers discuss the use of intersectional genetics involving selective transcriptional regulation mediated by either two viral systems or viral/transgenic mice models. Nicola et al., discuss the supraspinal and spinal circuitry involved in skilled forelimb patterning and the use of combining Cre-dependent tools with optogenetic or pharmacogenetic perturbation in transgenic mice to functionally dissect these circuits. Using similar 2-viral systems to selectively induce Tetanus toxin to silence specific neuronal populations, the article by Isa examines the circuitry involved in functional recovery of non-human primate reaching and grasping maneuvers mediated by C3/C4 propriospinal and supraspinal circuits. In general, plasticity associated with propriospinal neurons is thought to enable bypass relays around the lesion contributing to functional recovery. The article by Deng et al. further discusses the roles of propriospinal neurons in recovery and viral methods to induce plasticity and the functional mapping of the circuits to identify their contribution to recovery.
Although several articles in this collection highlight the therapeutic potential of viral vector-based candidates to enhance axonal regeneration, sprouting, and recovery of function, the paper by Campion et al. provides a cautionary tale of how overexpression of Akt leads to extensive regeneration and sprouting, but also the development of epilepsy due to hemimegalencephaly. This paper highlights the need for vigilance as we deploy powerful new technologies, and also hints that unanticipated pathophysiologies may limit recovery even when the long-sought goal of axon regeneration is achieved. This discovery has the potential of changing our thinking from “Our interventions aren't powerful enough” to “Our interventions may be too powerful because competing deleterious processes reduce recovery that might otherwise be achieved”.
It is clear from the scope of the articles in this Special Issue that tools and technologies to genetically modify cells and circuits of the spinal cord are advancing at a rapid pace. Gene modification after SCI is a burgeoning field, and if harnessed correctly has the potential to deliver new therapeutics as well as provide mechanistic insight into circuits and functions involved in injury and repair.