Gene therapy and respiratory neuroplasticity

Mantilla, Carlos B.

doi:10.1016/j.expneurol.2016.09.014

Cited by 4 publications

(3 citation statements)

References 92 publications

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“…Regeneration of central nervous system (CNS) axons after spinal cord injury (SCI) remains a clinical challenge, and while studies have shown that CNS regeneration is possible, reconnection to original secondary neuronal targets remains, as a whole, elusive (Alilain et al, 2011; Cafferty et al, 2008; Mantilla, 2017; Park et al, 2010; Vinit et al, 2006). The lack of a robust axonal regrowth response plays a significant role in persistent functional deficits following SCI.…”

Section: Introductionmentioning

confidence: 99%

Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI

Urban

Ghosh

Strojny

et al. 2018

Experimental Neurology

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Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality in individuals suffering from traumatic cervical spinal cord injury (SCI). Repair of CNS axons after SCI remains a therapeutic challenge, despite current efforts. SCI disrupts inspiratory signals originating in the rostral ventral respiratory group (rVRG) of the medulla from their phrenic motor neuron (PhMN) targets, resulting in loss of diaphragm function. Using a rat model of cervical hemisection SCI, we aimed to restore rVRG-PhMN-diaphragm circuitry by stimulating regeneration of injured rVRG axons via targeted induction of Rheb (ras homolog enriched in brain), a signaling molecule that regulates neuronal-intrinsic axon growth potential. Following C2 hemisection, we performed intra-rVRG injection of an adeno-associated virus serotype-2 (AAV2) vector that drives expression of a constitutively-active form of Rheb (cRheb). rVRG neuron-specific cRheb expression robustly increased mTOR pathway activity within the transduced rVRG neuron population ipsilateral to the hemisection, as assessed by levels of phosphorylated ribosomal S6 kinase. By co-injecting our novel AAV2-mCherry/WGA anterograde/trans-synaptic axonal tracer into rVRG, we found that cRheb expression promoted regeneration of injured rVRG axons into the lesion site, while we observed no rVRG axon regrowth with AAV2-GFP control. AAV2-cRheb also significantly reduced rVRG axonal dieback within the intact spinal cord rostral to the lesion. However, cRheb expression did not promote any recovery of ipsilateral hemi-diaphragm function, as assessed by inspiratory electromyography (EMG) burst amplitudes. This lack of functional recovery was likely because regrowing rVRG fibers did not extend back into the caudal spinal cord to synaptically reinnervate PhMNs that we retrogradely-labeled with cholera toxin B from the ipsilateral hemi-diaphragm. Our findings demonstrate that enhancing neuronal-intrinsic axon growth capacity can promote regeneration of injured bulbospinal respiratory axons after SCI, but this strategy may need to be combined with other manipulations to achieve reconnection of damaged neural circuitry and ultimately recovery of diaphragm function.

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Section: Introductionmentioning

confidence: 99%

Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI

Urban

Ghosh

Strojny

et al. 2018

Experimental Neurology

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“…The role of nerve cells of respiratory centers at all levels in the generation of respiratory rhythm and the regulation of respiratory movement is different, but they all complete the normal respiratory movement of the body through mutual coordination and mutual restriction among the centers at all levels. The autonomic respiratory rhythm is regulated above the spinal cord level, while the motor neurons innervating the respiratory muscle are located in the spinal cord and regulated by the highlevel central system [19,20] . Remimazolam had almost no inhibition on RR, but obvious inhibition on TV, propofol had obvious inhibition on TV and RR.…”

Section: Discussionmentioning

confidence: 99%

Comparison of effect of remimazolam and propofol on respiration of patients under deep sedation for colonoscopy: a prospective multicenter randomized controlled trial

Wang,

Zhan,

et al. 2023

Preprint

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Background: Remimazolam recently became available as a sedative. The comparison of the respiratory suppression effects of remimazolam and propofol under deep sedation for colonoscopy remains unclear. The goal of this study was to systemically compare the respiration profiles of the patients sedated with remimazolam and propofol at the comparable sedation level in the patients undergoing colonoscopy. Methods: Four hundred-fifty outpatients were randomly assigned to remimazolam (Group Rem, n = 225) and propofol (Group Pro, n = 225). The target sedation level was the modified Observer's Assessment of Alertness/Sedation ≤ 2. The primary outcome was elapsed time from anesthesia induction to first airway intervention. Secondary outcomes included incidence and severity of hypoxia and apnea, minute ventilation (MV), tidal volume (TV), and respiratory rate (RR). Results: The elapsed time from induction to the first airway intervention was 11 ± 8 min in Group Rem (n= 208) vs. 5 ± 6 min in Group Pro (n= 208, P <0.001). Patients in Group Rem required less frequent airway intervention and had a lower incidence of and shorter duration of apnea than patients in Group Pro (all P <0.001). MV at 1 min, 2 min, 4 min post-induction, and at the end of the procedure were higher in Group Rem than those in Group Pro (P < 0.001). Conclusions: Patients sedated with remimazolam vs. propofol during colonoscopy maintain improved respiration and require less frequent airway intervention, and has lower the incidence of adverse events.

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“…An emerging goal of contemporary translational research is to identify safe and effective therapeutic strategies for management and treatment of the long-term consequences of adaptations to chronic intermittent hypoxia (106,143,153,236). Pharmacological and immunological approaches and gene therapy are being actively considered (145,148,182,236,243). Ablation or denervation of the carotid bodies for resistant hypertension is also being evaluated in preclinical research (106).…”

Section: The "Erasure" Of Dysfunctional Cardiorespiratory Network Memoriesmentioning

confidence: 99%

Carotid Bodies and the Integrated Cardiorespiratory Response to Hypoxia

et al. 2018

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Advances in our understanding of brain mechanisms for the hypoxic ventilatory response, coordinated changes in blood pressure, and the long-term consequences of chronic intermittent hypoxia as in sleep apnea, such as hypertension and heart failure, are giving impetus to the search for therapies to "erase" dysfunctional memories distributed in the carotid bodies and central nervous system. We review current network models, open questions, sex differences, and implications for translational research.

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Gene therapy and respiratory neuroplasticity

Cited by 4 publications

References 92 publications

Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI

Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI

Comparison of effect of remimazolam and propofol on respiration of patients under deep sedation for colonoscopy: a prospective multicenter randomized controlled trial

Carotid Bodies and the Integrated Cardiorespiratory Response to Hypoxia

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