Viral vectors for therapy of neurologic diseases

Abstract

Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches – pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others – have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors – encoding a therapeutic gene or inhibitory RNA into a “gutted” viral capsid and supplying it to the nervous system – has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future.

Biodegradable and biocompatible cationic polymer delivering microRNA-221/222 promotes nerve regeneration after sciatic nerve crush

“…The gene delivery system, containing viral vectors, nonviral vectors, and engineered vectors, provides the means for transporting genetic material into the target cells. [5][6][7][8][9][10][11][12][13][14] Nonviral vectors have been thoroughly investigated in the past few years due to their lower immunogenicity and cytotoxicity, higher transfection efficiency and longer gene expression duration. 6,15,16 Polyethylenimine (PEI) is considered the gold standard for both in vivo and in vitro gene transfer in the field of cationic polymers because of its strong DNA condensation capacity and specific endosomolytic activity.…”

The challenges of developing a gene therapy for amyotrophic lateral sclerosis

“…Current vector options include AAV, adenovirus, herpesvirus (HSV), and lentivirus. Adenovirus and HSV both have had major improvements in recent years, but are not ideal choices for application in ALS primarily due to transient gene expression [16]. Lentiviral vectors elicit broad tissue tropisms and mediate long-term gene expression.…”

“…Lentiviral vectors elicit broad tissue tropisms and mediate long-term gene expression. In addition, pseudo-typed lentivirus is efficient for retrograde axonal transport [16,17]. The capacity for genome integration makes lentiviral vectors a favorable choice for ex vivo gene therapy, a paradigm which has shown therapeutic efficacy in small animal models [18].…”

“…Lentiviral vectors do have drawbacks that limit their use for in vivo gene therapy. These include limited volumetric spread from the site of infusion, risks of integrational mutagenesis, and only moderately-sized titers [16]. AAVs are considered the vector of choice for in vivo use due to their low-risk of integrational mutagenesis, diminished immunogenicity, high titers, and stable gene expression in non-dividing cells [16,20].…”

“…While retrograde axonal delivery (with AAV2, Rh10, or pseudotypedlentivirus) has shown success in small animal models, it has not scaled well to larger animal models and is not considered the first choice for translation [16,17,21]. In the domain of IV delivery, AAV9 is an option since it crosses the blood-brain barrier and demonstrates robust transduction of neuronal, glial, and endothelial cells [16,21]. The major limitations to IV delivery include off-target sequestration and, consequently, extremely high titer requirements [20].…”