AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

Abstract

Different glial cell types are found throughout the central (CNS) and peripheral nervous system (PNS), where they have important functions. These cell types are also involved in nervous system pathology, playing roles in neurodegenerative disease and following trauma in the brain and spinal cord (astrocytes, microglia, oligodendrocytes), nerve degeneration and development of pain in peripheral nerves (Schwann cells, satellite cells), retinal diseases (Müller glia) and gut dysbiosis (enteric glia). These cell type have all been proposed as potential targets for treating these conditions. One approach to target these cell types is the use of gene therapy to modify gene expression. Adeno-associated virus (AAV) vectors have been shown to be safe and effective in targeting cells in the nervous system and have been used in a number of clinical trials. To date, a number of studies have tested the use of different AAV serotypes and cell-specific promoters to increase glial cell tropism and expression. However, true glial-cell specific targeting for a particular glial cell type remains elusive. This review provides an overview of research into developing glial specific gene therapy and discusses some of the issues that still need to be addressed to make glial cell gene therapy a clinical reality.

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

“…Data on the detailed biology of HSV-1 infected neurons in the human TG will also be of benefit in the development of strategies to strengthen immune control of latent HSV-1 in ganglia. For example, it may be possible to improve intrinsic immunity of neurons and antiviral activities of SGC using vector delivered gene augmentation in a safe and cell type-dependent manner ( 197 , 198 ).…”

Enriched Environment Cues Suggest a New Strategy to Counteract Glioma: Engineered rAAV2-IL-15 Microglia Modulate the Tumor Microenvironment

“…AAV are considered optimal for human gene therapy as they are small and non-replicative, can transduce dividing and nondividing cells, are non-pathogenic in humans, and can determine long-lasting changes in gene expression. Importantly, AAV have been used to target several cell types, including microglia ( 24 , 48 ).…”

“…In this study, we explored the potential use of microglia engineered to express IL-15 upon infection with a recombinant adeno-associated virus serotype 2 (rAAV2) carrying IL-15 (rAAV2-IL-15), to simulate the effect of EE on glioma. AAV are considered safe for human gene therapy and have been successfully used to target several cell types within the central (CNS) and peripheral nervous systems (PNS), including neurons, oligodendrocytes, astrocytes, Müller glia, Schwann cells, and also microglia ( 24 ). We demonstrated that rAAV2-IL-15 microglia increase the viability of cocultured NK cells, without affecting their activation state in vitro .…”

Genetic Constructs for the Control of Astrocytes’ Activity

“…Application of AAVs, specifically AAV8 and AAV9, provides variable results depending on experimental conditions, AAV production protocols, and region- and cell-specific characteristics in the injection area. Application of natural AAV serotypes for cell-specific transduction has obvious limitations that can be bypassed by generating synthetic “designer” AAV variants with specified, enhanced properties through rational engineering of AAV capsids or using a directed evolution approach [ 67 , 73 , 150 , 151 , 152 ]. Realizing these strategies for developing novel synthetic serotypes for astrocytic targeting has excellent potential for basic and translational neuroscience.…”