Differential Adeno-Associated Virus Mediated Gene Transfer to Sensory Neurons following Intrathecal Delivery by Direct Lumbar Puncture

Vulchanova, Lucy; Schuster, Daniel J.; Belur, Lalitha R.; Riedl, Maureen; Podetz-Pedersen, Kelly M.; Kitto, Kelley F.; Wilcox, George L.; McIvor, R. Scott; Fairbanks, Carolyn A.

doi:10.1186/1744-8069-6-31

Cited by 101 publications

(119 citation statements)

References 37 publications

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“…Although gene expression was found in the sciatic nerve after AAV vector delivery into the DRG, this was mainly in axons and DRG, and not in Schwann cells as in our study (23). Cell specificity is crucial for exogenous expression of neuropathy-associated genes such as Cx32, given that inherited demyelinating neuropathies result mostly from cell-autonomous loss of function in Schwann cells (35,36).…”

Section: Discussionmentioning

confidence: 75%

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked CharcotMarie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.demyelinating neuropathy | Charcot-Marie-Tooth disease | connexin32 | peripheral nerve | gene therapy

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Section: Discussionmentioning

confidence: 75%

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1I ). It has been reported that drugs can be predominantly delivered into DRG neurons by direct lumbar puncture (Vulchanova et al, 2010;Duan et al, 2012). LP injection of SD-208 (5 g/20 l) had no effect on PWL in naive rats (Fig.…”

Section: Tgf-␤1 and Tgf␤rs Are Involved In Bone Cancer Painmentioning

confidence: 99%

Peripheral TGF-β1 Signaling Is a Critical Event in Bone Cancer-Induced Hyperalgesia in Rodents

Zhang

Duan

et al. 2013

J. Neurosci.

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Pain is the most common symptom of bone cancer. TGF-␤, a major bone-derived growth factor, is largely released by osteoclast bone resorption during the progression of bone cancer and contributes to proliferation, angiogenesis, immunosuppression, invasion, and metastasis. Here, we further show that TGF-␤1 is critical for bone cancer-induced pain sensitization. We found that, after the progression of bone cancer, TGF-␤1 was highly expressed in tumor-bearing bone, and the expression of its receptors, TGF␤RI and TGF␤RII, was significantly increased in the DRG in a rat model of bone cancer pain that is based on intratibia

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“…Here the potential role of the pia mater in establishing such a barrier to particulates and larger molecules in the CSF has been noted in humans and dogs [438][439][440]. Techniques to increasethat movement have been proposed,including the use of hypertonic solutions [441].…”

Section: Gene-based Approachesmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Differential Adeno-Associated Virus Mediated Gene Transfer to Sensory Neurons following Intrathecal Delivery by Direct Lumbar Puncture

Cited by 101 publications

References 37 publications

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Peripheral TGF-β1 Signaling Is a Critical Event in Bone Cancer-Induced Hyperalgesia in Rodents

Current and Future Issues in the development of spinal agents for the management of pain

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