Gene transfer into the central nervous system using herpes simplex virus-1 vectors (original) (raw)
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Herpes simplex virus vectors for gene transfer to the nervous system
1997
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 transfer to brain using herpes simplex virus vectors
Annals of Neurology, 1994
Herpes simplex virus type 1 represents an ideal candidate for development as a vehicle for gene transfer to postmitotic neurons of the central nervous system. The natural biology of this virus makes it well suited for this purpose as it is capable of infecting a variety of neuronal cell types in the brain where the viral genome can persist indefinitely in a latent state. In latency, the viral lytic genes are transcriptionally silent and a unique set of latency-associated transcripts are expressed. Two impediments to using herpes simplex virus vectors must be overcome: (1) A noncytotoxic mutant virus backbone must be engineered, and (2) a suitable promoter-regulator that stably expresses foreign genes from the vector genome during latency must be constructed. Deletion of specific immediate early genes from the vector can render the virus nontoxic to neurons in culture and in vivo following stereotactic inoculation into specific regions of the brain. Because these viruses cannot replicate, they enter latency on infection of central nervous system neurons. A number of viral and cellular promoters have been tested for their ability to express genes during latency. Strong viral promoters and neurospecific promoters display transient activity. Although the promoter regions for the latencyassociated transcripts are highly active in the peripheral nervous system, they show low-level but persistent activity in the brain. Experiments are in progress to exploit RNA polymerase I11 gene promoters or novel recombinant promoters capable of auto-inducing their own expression in order to increase gene expression during latency in brain neurons.
Molecular and Cellular Neuroscience, 1991
We report here the first use of a herpes simplex virus defective viral vector for the transfer and expression of a foreign gene in the adult rat brain in viva. Defective vectors offer unique advantages over other systems. Our vector genome consists of multiple copies of a plasmidbased amplicon, with a human cytomegalovirus promoter and 1acZ gene as a reporter. Helper functions were provided by an HSVl mutant incapable of replication at physiological temperatures. The resulting defective viral vector was stereotaxically microinjected into rat hippocampus and hypothalamus, and cells expressing functional /3-galactosidase were detected in both areas. Expression was confined to regions at or near the site of injection. Positive cells were identified by 18 hr following injection, and expression was still detectable after 2 weeks. All animals survived with no behavioral, gross, or microscopic anatomical evidence of a virulent neurologic infection.
Gene transfer into neurones for the molecular analysis of behaviour: focus on herpes simplex vectors
Trends in Neurosciences, 2000
The use of viral vectors to transfect genes into specific brain-cell populations is a novel approach that can be used to investigate the molecular and cellular basis of brain function. Ideal vectors should be targetable and capable of regulated transgene expression. From the viral vectors developed so far, this article focuses on herpes simplex virus 1 (HSV-1)-based vectors. HSV-1 vectors can be engineered for gene transfer to the brain, which makes them suitable for neuroscience research applications.In particular,genetic manipulations of the virus can almost eliminate toxicity and allow expression of multiple transgenes simultaneously. In some instances, transfection of selected neuronal populations is also possible. Specific alterations in behaviour and in disease models have been described after the viral-vector-mediated expression of specific genes within highly localized brain regions.
Therapeutic Gene Transfer to the Nervous System Using Viral Vectors
Journal of Neurovirology, 2003
The past few years have been marked by substantial progress in preclinical studies of therapeutic gene transfer for neurologic disease using viral-based vectors. In this article, the authors review the data regarding (1) treatment of focal neuronal degeneration, exemplified by Parkinson disease, ischemia, and trauma models; (2) treatment of global neurologic dysfunction, exemplified by the mucopolysaccharidoses and other storage diseases; (3) peripheral nervous system diseases including motor neuron disease and sensory neuropathies; and (4) the use of vectors expressing neurotransmitters to modulate functional neural activity in the treatment of pain. The results suggest that a number of different viral vectors may be appropriate for gene transfer to the central nervous system for specific disease processes, and that for the peripheral nervous system herpes simplex virus-based vectors appear to have special utility. The results of the first human gene therapy trials for neurologic disease, which are just now beginning, will be crucial in defining the next step in the development of this therapy. Journal of NeuroVirology (2003) 9, 165-172.
Molecular analysis of behavior by gene transfer into neurons with herpes simplex vectors
Brain Research, 1999
One goal of neuroscience is to define the molecular and cellular basis for behavior and neurological diseases. A novel approach to this problem is based on the use of viral vectors to transfect specific genes into specific brain cell populations. This review focuses on herpes simplex-based vectors. Major advances have recently been made to improve the characteristics of these vectors, in particular to reduce their toxicity, to modulate the greatness and the time-course of transgene expression, to precisely target specific cell populations, and to transfer multiple genes. Much remains to be done to obtain robust and prolonged transgene expression. However, specific alterations in the behavior and in disease models have already been described following the herpes simplex vector-mediated expression of specific genes within highly localized brain areas. Therefore, this research strategy is likely to provide new clues on the cellular and molecular basis of behavior and of neurological diseases. q
Drug inducible transgene expression in brain using a herpes simplex virus vector
Gene Therapy, 1998
The ability to regulate transgene expression is likely to be ture half maximal expression was achieved with 10 −8 M important in the use of gene transfer to treat diseases of RU486, and maximal expression was achieved by 24 h. the central nervous system (CNS). In order to achieve Following stereotactic inoculation of the vector into rat regulatable gene expression we created a replication-hippocampus, expression was increased 150-fold by i.p. incompetent genomic herpes simplex vector containing a administration of RU486. This demonstrates that the RU486-inducible transactivator and a lacZ reporter gene RU486 system functions as a tight on/off switch for regunder transcriptional control of a minimal promoter.
Helper virus-free transfer of herpes simplex virus type 1 plasmid vectors into neural cells
Journal of virology, 1996
Herpes simplex virus type 1 (HSV-1) plasmid vectors have promise for genetic intervention in the brain, but several problems caused by the helper virus have compromised their utility. To develop a helper virus-free packaging system for these vectors, the DNA cleavage/packaging signals were deleted from a set of cosmids that represents the HSV-1 genome. Following cotransfection into cells, this modified cosmid set supported replication and packaging of vector DNA. However, in the absence of the DNA cleavage/packaging signals, the HSV-1 genome was not packaged, and consequently vector stocks were free of detectable helper virus. In the absence of helper virus, the vectors efficiently infected rat neural cells in culture or in the brain with minimal cytopathic effects. beta-galactosidase-positive cells were observed for at least 1 month in vivo, and vector DNA persisted for this period. This system may facilitate studies on neuronal physiology and potential therapeutic applications.