Herpes Simplex Virus Vectors for Gene Transfer to the Central Nervous System

Abstract

Neurodegenerative diseases (NDs) have a profound impact on human health worldwide and their incidence is predicted to increase as the population ages. ND severely limits the quality of life and leads to early death. Aside from treatments that may reduce symptoms, NDs are almost completely without means of therapeutic intervention. The genetic and biochemical basis of many NDs is beginning to emerge although most have complex etiologies for which common themes remain poorly resolved. Largely relying on progress in vector design, gene therapy is gaining increasing support as a strategy for genetic treatment of diseases. Here we describe recent developments in the engineering of highly defective herpes simplex virus (HSV) vectors suitable for transfer and long-term expression of large and/or multiple therapeutic genes in brain neurons in the complete absence of viral gene expression. These advanced vector platforms are safe, non-inflammatory, and persist in the nerve cell nucleus for life. In the near term, it is likely that HSV can be used to treat certain NDs that have a well-defined genetic cause. As further information on disease etiology becomes available, these vectors may take on an expanded role in ND therapies, including gene editing and repair.

Gene Therapy Leaves a Vicious Cycle

“…For example, Vero-7b cell line is capable of providing in trans the proteins encoded by deleted viral genes (165). They are safe and non-inflammatory advanced vector platforms known to persist and express in the nerve cells for life and therefore used to treat neuropathic, inflammatory, and cancer-associated pain (166–168). The helper-dependent HSV vectors, or amplicon vectors, carry deletions in one or more non-essential genes and retain the ability to replicate in vitro but are compromised in vivo in a context-dependent manner (169, 170).…”

Optogenetic and chemogenetic therapies for epilepsy

“…These are even larger (200 nm), and exist as replicating, replication-deficient and amplicon vectors (lacking all but the packaging viral DNA) (Simonato et al, 2013). The replication and replication-deficient vectors are potentially cytotoxic, although novel strategies are being developed to overcome this (Artusi et al, 2018). The HSV amplicon has a lipid envelope, is strongly neurotropic, and forms episomes.…”

“…Its main advantage is the ability to carry up to 150 kb DNA (Choudhury et al, 2017). The main disadvantages are difficulties in amplicon production with cross-contamination from helper viruses, potentially leading to cytotoxicity and immunogenicity (Artusi et al, 2018).…”

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

“…Viral gene therapy vectors specifically designed for NDD applications should be able to efficiently cross the blood-brain barrier (BBB), if delivered by iv infusion [44,49], and support an efficient transgene expression, regardless of aberrant cell signaling caused by the accumulation of toxic proteins or restoration of an autophagic state in neuronal cells [50]. For instance, vectors based on genomes of adeno-associated virus (AAV) [44,49,[51][52][53][54][55][56], lentivirus [57], type 1 herpes simplex virus [58], and Semliki Forest virus (SFV) [59] have been broadly used for neuron targeting. Extensive use of the above viruses in neuroscience is dictated by their natural ability to efficiently and selectively transduce and provide high transgene expression in neurons.…”