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Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain.

ABSTRACT: Lumbar puncture (LP) is an attractive route to deliver drugs to the nervous system because it is a safe bedside procedure. Its use for gene therapy has been complicated by poor vector performance and failure to target neurons. Here we report highly effective gene transfer to the primary sensory neurons of the dorsal root ganglia (DRGs) with self-complementary recombinant adeno-associated virus serotype 8 (sc-rAAV8) modeling an LP. Transgene expression was selective for these neurons outlining their cell bodies in the DRGs and their axons projecting into the spinal cord. Immunohistochemical studies demonstrated transduction of cells positive for the nociceptive neuron marker vanilloid receptor subtype 1, the small peptidergic neuron markers substance P and calcitonin gene-related peptide, and the nonpeptidergic neuron marker griffonia simplicifolia isolectin B4. We tested the efficacy of the approach in a rat model of chronic neuropathic pain. A single administration of sc-rAAV8 expressing the analgesic gene prepro-beta-endorphin (ppbetaEP) led to significant (P < 0.0001) reversal of mechanical allodynia for >/=3 months. The antiallodynic effect could be reversed by the mu-opioid antagonist naloxone 4 months after gene transfer (P < 0.001). Testing of an alternative nonopioid analgesic gene, IL-10, alone or in combination with ppbetaEP was equally effective (P < 0.0001). All aspects of the procedure, such as the use of an atraumatic injection technique, isotonic diluent, a low-infusion pressure, and a small injection volume, are consistent with clinical practice of intrathecal drug use. Therefore, gene transfer by LP may be suitable for developing gene therapy-based treatments for chronic pain.

SUBMITTER: Storek B

PROVIDER: S-EPMC2242718 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain.

Storek Benjamin B Reinhardt Matthias M Wang Cheng C Janssen William G M WG Harder Nina M NM Banck Michaela S MS Morrison John H JH Beutler Andreas S AS

Proceedings of the National Academy of Sciences of the United States of America 20080122 3

Lumbar puncture (LP) is an attractive route to deliver drugs to the nervous system because it is a safe bedside procedure. Its use for gene therapy has been complicated by poor vector performance and failure to target neurons. Here we report highly effective gene transfer to the primary sensory neurons of the dorsal root ganglia (DRGs) with self-complementary recombinant adeno-associated virus serotype 8 (sc-rAAV8) modeling an LP. Transgene expression was selective for these neurons outlining th ...[more]

PMID: 18215993

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Project description:Background Lumbar puncture (LP) remains an essential diagnostic procedure for neurological and infectious diseases. However, it remains a source of anxiety to patients and families. This research aimed to assess the impact of a newly developed educational simplified video about LP, in the parents’ native language, that is tailored to their social background and beliefs and to assess whether it can facilitate their consent for the procedure. Methods This prospective, interventional study was conducted at the outpatient pediatric clinics at a teaching hospital. The conventional arm used verbal explanation about LP. The second method utilized a standardized video, having the same information as the conventional arm, with streaming of graphic depictions. Parents’ knowledge and perceived LP risks were measured before and after the intervention. Results Two hundred and one parents were enrolled, with no significant differences in the socio-demographic and baseline characteristics. Both verbal and video-based counseling were found to provide a statistically significant increase in knowledge scores, and a Wilcoxon signed-rank test showed that knowledge gains for both groups were statistically significant (Verbal Explanation: W = 2693, n = 83, P < .001 and Video: W = 5538, n = 117, P < .001). However, the conventional verbal counseling resulted in more consistent gain of knowledge (SD = 14.5) as compared to the video group (SD = 18.94). The video group reported higher perceived risk (Mean 8.2, SD 3.59) than the verbal explanation group (Mean 7.12, SD 2.51). The less educated parents perceived LP procedure to be of significantly higher risk after watching the video (P < .001). It was found that 73.6% of persons with perceived intention to refuse LP changed their opinion after either of the counseling interventions, with significant opinion difference pre- and post-counseling intervention (P value .002). Conclusions Video education in parents’ native language about LP is as effective as conventional verbal education for informed consent, with the additional advantage of reproducibility and more illustrations to give parents better insight. However, this video should be followed by direct interaction with parents to ensure their full understanding and address any further concerns.

Project description:BackgroundHeadache is disabling and prevalent in idiopathic intracranial hypertension. Therapeutic lumbar punctures may be considered to manage headache. This study evaluated the acute effect of lumbar punctures on headache severity. Additionally, the effect of lumbar puncture pressure on post-lumbar puncture headache was evaluated.MethodsActive idiopathic intracranial hypertension patients were prospectively recruited to a cohort study, lumbar puncture pressure and papilloedema grade were noted. Headache severity was recorded using a numeric rating scale (NRS) 0-10, pre-lumbar puncture and following lumbar puncture at 1, 4 and 6 hours and daily for 7 days.ResultsFifty two patients were recruited (mean lumbar puncture opening pressure 32 (28-37 cmCSF). At any point in the week post-lumbar puncture, headache severity improved in 71% (but a small reduction of -1.1?±?2.6 numeric rating scale) and exacerbated in 64%, with 30% experiencing a severe exacerbation???4 numeric rating scale. Therapeutic lumbar punctures are typically considered in idiopathic intracranial hypertension patients with severe headaches (numeric rating scale???7). In this cohort, the likelihood of improvement was 92% (a modest reduction of headache pain by -3.0?±?2.8 numeric rating scale, p?=?0.012, day 7), while 33% deteriorated. Idiopathic intracranial hypertension patients with mild (numeric rating scale 1-3) or no headache (on the day of lumbar puncture, prior to lumbar puncture) had a high risk of post- lumbar puncture headache exacerbation (81% and 67% respectively). Importantly, there was no relationship between lumbar puncture opening pressure and headache response after lumbar puncture.ConclusionFollowing lumbar puncture, the majority of idiopathic intracranial hypertension patients experience some improvement, but the benefit is small and post-lumbar puncture headache exacerbation is common, and in some prolonged and severe. Lumbar puncture pressure does not influence the post-lumbar puncture headache.

Project description:Neuroinflammation is evident and one of the primary induced responses after central nervous system (CNS) injury, lumbar puncture and CNS surgery. In rare cases, complications could arise after the lumbar puncture or CNS surgery leading to inflammation, bleeding or other problems such as cerebrospinal fluid (CSF) leakage. The present dataset describes the occurrence of such a condition after the dura breakage or postoperative complication leading to the development of neuroinflammation in the adult Wistar rats. Therefore, objective of the study is to report such a rare condition and detect the most reliable glial proteins upregulated 2-3 weeks after the lumbar puncture which may help the neuroscience community to a better understanding their cause of action. In response to neuroinflammation, glial cells leak into the extracellular space, where they can be identified in the CSF or serum and may act as diagnostic biomarkers. Laminectomy was performed at the thoraco-lumbar (T12-L1) region and the dura was punctured. After that, the exposed part was covered with silica gel and adhesive followed by dental cement. The skin was closed using sterile sutures. After, the rats were given buprenorphine (0.05 mg/kg, every 8 h for 3 days) and carprofen (5 mg/kg, once a day for 5 days) as analgesic and anti-inflammatory and baytril (5 mg/kg, once a day for 10 days) as antibiotic drugs. Note, the buprenorphine and lidocaine were also given before starting the procedure. After the laminectomy, the functional outcomes of the rats were tested (starting from the day of surgery to the last day) and the rats which were locomoting normally using all the limbs were included in the study. In case of any decompression, the functional outcomes showing any kind of laming or partial paralysis of hindlimbs were excluded from the study. Unexpected neuroinflammation has occurred 2-3 weeks after performing the given procedure. Data presented in the article implicate active microglia measured by using protein biomarker such as Iba-1 [1, 3] and astrocytes measured by using Glial fibrillary acidic protein (GFAP) [2, 3] and S100 (strongly targets S100B and weakly A1) [7, 8] in the CSF collected two-three weeks after the laminectomy and dura breakage from the adult rats. Later paraformaldehyde (PFA) fixed spinal cord slices were also collected from the animals and immunolabelled with the same biomarkers. Western blots were performed with the collected CSF which showed high expression of glial markers such as GFAP, Iba-1 and S100 which has shown to target S100B with no expression of A1 (or A2, play an important role in neuroprotection) astrocytes which have recently been shown to be produced by microglia at the site of injury [9]. However, S100B [10] and GFAP [2] are known to be adequately discharged by the distinct cells in stress conditions which seems to occur in the present report. In addition, the spinal slices immunolabelled with the same biomarkers also showed increased expression of glia. Cross-talk between microglia-astrocyte in CNS stress is crucial for the neurons to survive and function after the injury. Reactive microglia (shown by high Iba-1 expression) leading to microgliosis comprise the first line of defense to phagocytose the dead cells [11]. Astrocytes act as the second line of defense leading to a process known as astrogliosis and upregulate GFAP and S100B to limit the damage [12]. Further studies are needed to explain the molecular mechanism/s of different astrocytes release such as A2 and their interaction with microglia after the lumbar puncture.

Project description:Among the multiple causes of chronic low back pain, axial and discogenic pain are common. Various modalities of treatments are utilized in managing discogenic and axial low back pain including epidural injections. However, there is a paucity of evidence regarding the effectiveness, indications, and medical necessity of any treatment modality utilized for managing axial or discogenic pain, including epidural injections. In an interventional pain management practice in the US, a randomized, double-blind, active control trial was conducted. The objective was to assess the effectiveness of lumbar interlaminar epidural injections of local anesthetic with or without steroids for managing chronic low back pain of discogenic origin. However, disc herniation, radiculitis, facet joint pain, or sacroiliac joint pain were excluded. Two groups of patients were studied, with 60 patients in each group receiving either local anesthetic only or local anesthetic mixed with non-particulate betamethasone. Primary outcome measures included the pain relief-assessed by numeric rating scale of pain and functional status assessed by the, Oswestry Disability Index, Secondary outcome measurements included employment status, and opioid intake. Significant improvement or success was defined as at least a 50% decrease in pain and disability. Significant improvement was seen in 77% of the patients in Group I and 67% of the patients in Group II. In the successful groups (those with at least 3 weeks of relief with the first two procedures), the improvement was 84% in Group I and 71% in Group II. For those with chronic function-limiting low back pain refractory to conservative management, it is concluded that lumbar interlaminar epidural injections of local anesthetic with or without steroids may be an effective modality for managing chronic axial or discogenic pain. This treatment appears to be effective for those who have had facet joints as well as sacroiliac joints eliminated as the pain source.

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Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain.

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Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain.

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