Gene Therapy Using Replication-Defective Herpes Simplex Virus Vectors Expressing Nerve Growth Factor in a Rat Model of Diabetic Cystopathy

Sasaki, Kenji; Chancellor, Michael B.; Goins, William F.; Phelan, Michael W.; Glorioso, Joseph C.; Groat, William C. de; Yoshimura, Naoki

doi:10.2337/diabetes.53.10.2723

Cited by 88 publications

(82 citation statements)

References 42 publications

(47 reference statements)

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“…141 This observation may be exploited for the development of therapies for the autonomic neuropathy associated with diabetes. 142 In other studies, somatosensory neurons of rats were transduced by peripheral inoculation with a vector expressing neurotrophin-3 (NT-3). 143 Pretreatment with the NT-3-expressing vector significantly protected sensory axons from the toxic effects of pyridoxine overdose, demonstrated by behavioral, morphological, and electrophysiological analyses.…”

Section: Exploiting Axonal Transport For Delivery Of Therapeutic Agentsmentioning

confidence: 99%

HSV trafficking and development of gene therapy vectors with applications in the nervous system

et al. 2005

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Herpes simplex virus type 1 (HSV-1) is a neurotropic doublestranded DNA virus that causes cold sores, keratitis, and rarely encephalitis in humans. Nonpathogenic HSV-1 gene transfer vectors have been generated by elimination of viral functions necessary for replication. The life cycle of the native virus includes replication in epithelial cells at the site of initial inoculation followed by retrograde axonal transport to the nuclei of sensory neurons innervating the area of cutaneous primary infection. In this review, we summarize the current understanding of the molecular basis for HSV cell entry, nuclear transport of the genome, virion egress following replication, and retrograde and anterograde axonal transport in neurons. We discuss how each of these properties has been exploited or modified to allow the generation of gene transfer vectors with particular utility for neurological applications. Recent advances in engineering virus entry have provided proof of principle that vector targeting is possible. Furthermore, significant and potentially therapeutic modifications to the pathological responses to various noxious insults have been demonstrated in models of peripheral nerve disease. These applications exploit the natural axonal transport mechanism of HSV, allowing transgene expression in the cell nucleus within the inaccessible trigeminal ganglion or dorsal root ganglion, following the noninvasive procedure of subcutaneous vector inoculation. These findings demonstrate the importance of understanding basic virology in the design of vector systems and the powerful approach of exploiting favorable properties of the parent virus in the generation of gene transfer vectors. Gene Therapy (2005) 12, 891-901.

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Section: Exploiting Axonal Transport For Delivery Of Therapeutic Agentsmentioning

confidence: 99%

HSV trafficking and development of gene therapy vectors with applications in the nervous system

et al. 2005

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“…Previous studies demonstrate the utility of replication-defective HSV vectors in the treatment of numerous neurodegenerative disorders of the PNS through the expression of trophic factors, such as nerve growth factor (NGF), neurotrophin 3 (NT-3) and GDNF, [37][38][39][40][41][42][43][44][45] and support their use as therapeutic agents in treating neurological complications of ED. In addition, we have recently demonstrated that replication-defective HSV vectors expressing NT-3 are effective in improving erectile function in rats with chemically induced diabetes mellitus (DM) when the vectors were injected around the cavernous nerve 4 weeks after the induction of DM, 39 although it is not known whether similar gene transfer techniques would be effective for the treatment of ED induced by nerve injury.…”

Section: Introductionmentioning

confidence: 99%

Herpes simplex virus vector-mediated delivery of glial cell line-derived neurotrophic factor rescues erectile dysfunction following cavernous nerve injury

Kato

Wolfe²,

Coyle

et al. 2007

Gene Ther

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Erectile dysfunction (ED) is frequently associated with injury to the cavernous nerve sustained during pelvic surgery. Functional recovery from cavernous nerve injury is generally incomplete and occurs over an extended time frame. We employed a therapeutic gene transfer approach with herpes simplex virus (HSV) vector expressing glial cell line-derived neurotrophic factor (GDNF). Rat cavernous nerve was injured bilaterally using a clamp and dry ice. For HSV-treated groups, 20 ml of purified vector stock was administered directly to and around the damaged nerve. Delivery of an HSV vector expressing both green fluorescent protein (GFP) and lacZ (HSV-LacZ) was used as a control. Intracavernous pressure along with systemic arterial pressure (ICP/AP) was measured 2 and 4 weeks after the nerve injury. Fluorogold (FG) was injected into the penile crus 7 days before killing to assess nerve survival. Approximately 60% of major pelvic ganglion (MPG) cells were GFP positive after viral administration. At 4 weeks after nerve injury, rats treated with HSV-GDNF exhibited significant recovery of ICP/AP compared with control vector or untreated groups. The HSV-GDNF group also yielded more FG-positive MPG cells than the control vector group. HSV vector-mediated delivery of GDNF presents a viable approach for the treatment of ED following cavernous nerve injury.

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“…Although data regarding bladder function are lacking for DM patients, experimental evidence suggests that NGF improves diabetic bladder dysfunction in the decompensated phase. NGF gene therapy by herpes-virus-mediated NGF gene delivery into the bladder results in long-term elevation of NGF bladder levels, preventing excessive increases in bladder capacity and reducing postvoid residual volume in diabetic rats (541). These data provide interventional evidence for a causal role of NGF in the development of diabetic cystopathy.…”

Section: Diabetes Mellitus and Detrusor Underactivitymentioning

confidence: 64%

Neural Control of the Lower Urinary Tract

2009

Encyclopedia of Neuroscience

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This article summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract. The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. The neural control of micturition is organized as a hierarchical system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brain stem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brain stem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary micturition, leading to urinary incontinence. Neuroplasticity underlying these developmental and pathological changes in voiding function is discussed.

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Gene Therapy Using Replication-Defective Herpes Simplex Virus Vectors Expressing Nerve Growth Factor in a Rat Model of Diabetic Cystopathy

Cited by 88 publications

References 42 publications

HSV trafficking and development of gene therapy vectors with applications in the nervous system

HSV trafficking and development of gene therapy vectors with applications in the nervous system

Herpes simplex virus vector-mediated delivery of glial cell line-derived neurotrophic factor rescues erectile dysfunction following cavernous nerve injury

Neural Control of the Lower Urinary Tract

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