Viral vectors for gene delivery to the central nervous system

Abstract

The potential benefits of gene therapy for neurological diseases such as Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), Epilepsy, and Alzheimer’s are enormous. Even a delay in the onset of severe symptoms would be invaluable to patients suffering from these and other diseases. Significant effort has been placed in developing vectors capable of delivering therapeutic genes to the CNS in order to treat neurological disorders. At the forefront of potential vectors, viral systems have evolved to efficiently deliver their genetic material to a cell. The biology of different viruses offers unique solutions to the challenges of gene therapy, such as cell targeting, transgene expression and vector production. It is important to consider the natural biology of a vector when deciding whether it will be the most effective for a specific therapeutic function. In this review, we outline desired features of the ideal vector for gene delivery to the CNS and discuss how well available viral vectors compare to this model. Adeno-associated virus, retrovirus, adenovirus and herpesvirus vectors are covered. Focus is placed on features of the natural biology that have made these viruses effective tools for gene delivery with emphasis on their application in the CNS. Our goal is to provide insight into features of the optimal vector and which viral vectors can provide these features.

Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain

“…Owing to the high sensitivity of neurons to chemical and biological insults and their poor accessibility for nonviral vectors, especially in vivo, targeting viruses with transduction of beneficial genes has been viewed as a promising therapeutic strategy. Yet, remaining conceptual and methodical challenges constrained applications of viral technologies to neurobiology research and preclinical studies, with their clinical use becoming available only recently [49,50]. One of the key objectives of AD therapy is protection of BFCNs and synapses from pathological insult, and restoration, or perhaps enhancement, of cholinergic functions [51][52][53].…”

Current developments in gene therapy for amyotrophic lateral sclerosis

“…However, LV provides a long-term transgene expression, a moderate scalable production of pure virus and can infect post-mitotic cells in the CNS efficiently as well as glial cells. These characteristics make them the second most commonly used viral vector for gene therapy in the CNS [80].…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…For effective RNAi delivery via the blood, the presence of the blood-brain barrier (BBB) is an obstacle that must be overcome, while, for direct injection into the brain, steps must be taken to avoid toxic or inflammatory reactions. An ideal delivery system for RNAi to the CNS should be minimally immunogenic, nontoxic, target specific cells of the CNS, knockdown the specific target mRNA efficiently, and be easy to manufacture [38]. Two major types of delivery systems have emerged over the years, differing in production, safety, and efficacy.…”

“…There are a number of viral vectors that can be used for gene delivery to the CNS, as discussed in a prior review [38]. The two main viral vector systems that are used to Small interfering RNAs (siRNAs) that are complexed or delivered directly into cells, enter the pathway at the Dicer-to-RISC stage or can be incorporated directly into RISC to carry out gene silencing transduce the CNS are lentiviruses (LV) and adenoassociated viruses (AAV).…”

“…Additionally, AAV rarely integrates into the genome. In general, AAVs are non-pathogenic and have low immunogenic properties, which make them ideal for gene delivery in vivo [38]. AAVs confer robust expression, efficiently transduce neurons and other cell types, and, in the absence of an immune response to what is being expressed, can afford long-term expression [59][60][61].…”