Intrathecal Substance P-Saporin in the Dog

Wiese, Ashley J.; Rathbun, Michael; Butt, Mark T.; Malkmus, Shelle; Richter, Philip J.; Osborn, Kent G.; Xu, Qing; Veesart, Samantha L.; Steinauer, Joanne; Higgins, Denise; Lappi, Douglas A.; Russell, Brian; Yaksh, Tony L.

doi:10.1097/aln.0b013e3182a95164

“…For these reasons, future studies may need to address the issue of AAV escape from the IT space by alternate procedure of IT vector delivery such as by interventional radiology assisted lumbar puncture. Such experiments may be a valuable addition to the use of the long-standing, “gold standard” dog model that was used in the present study 30,39–43 .…”

Section: Resultsmentioning

confidence: 99%

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs

Pleticha

¹

,

Malkmus

²

,

Heilmann

³

et al. 2014

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Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). While this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or anti-allodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an anti-allodynic cytokine, for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5×1012 genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be anti-allodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the dogs’ CSF and serum. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals suggesting a strong case for further development towards clinical testing.

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“…, receptor or enzyme protein). The development of such data is important not only because it demonstrates confirmatory effects in another species, it has the practical benefit of being able to show the safety data studies to be constructed so as to define safety as multiples of a therapeutically effective dose in a large spinal cord (see, for example [390]).…”

Section: Current Spinal Agentsmentioning

confidence: 99%

Current and Future Issues in the Development of Spinal Agents for the Management of Pain

Yaksh

¹

,

Fisher²,

Hockman³

et al. 2017

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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.

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“…Intrathecal sP-saporin has been shown to lead to a robust change in a variety of pain states in several species including the rodent [389] and dog [261]. Large animal safety studies have shown target engagement after intrathecal delivery showing local knockdown of spinal NK1-r protein and message [390]. Importantly, at high concentrations motor dysfunction was observed that reflected upon the presence of NK1-r in motor neurons in the dog.…”

Section: Toxins Coupled To Agonists For G-protein-coupled Receptorsmentioning

confidence: 98%

“…Where feasible, the drug dosing should be shown to have appropriate target engagement (e.g., behavioral endpoints, CSF concentrations, and knock-out of target marker (e.g., receptor or enzyme protein). The development of such data is important not only because it demonstrates confirmatory effects in another species, it has the practical benefit of being able to show the safety data studies to be constructed so as to define safety as multiples of a therapeutically effective dose in a large spinal cord (see, for example [390]). …”

Section: Intrathecal Drug Safety Evaluationmentioning

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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Intrathecal Substance P-Saporin in the Dog

Abstract: Intrathecal 15-µg SP-SAP reduced dorsal, but not ventral, NK1-r (+) neurons at the spinal level of delivery with minimal side effects, whereas 150-µg SP-SAP resulted in motor neuron toxicity.

Cited by 36 publications

References 46 publications

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs

Current and Future Issues in the Development of Spinal Agents for the Management of Pain

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

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