Biology subjects

Hoang, J. D.

Publications and source records attributed to Hoang, J. D..

4 recordsLinked to original sources

bioRxiv2025

AAVs Targeting Human Carbonic Anhydrase IV Enhance Gene Delivery to the Brain

Clinically approved gene therapies based on natural adeno-associated virus (AAV) serotypes have restricted applications, particularly in the brain, due to their poor targeting, high dose requirements, and resulting safety concerns. Directed evolution of enhanced AAV capsids in mice or non-human primates (NHPs) has resulted in markedly improved performance in those species, but inter-species differences present a serious challenge for translating these vectors into human therapies. Here, we engineer AAVs to target human carbonic anhydrase IV (CA-IV), a recently identified blood-brain barrier (BBB) transcytosis receptor. Among known transcytosis receptors, CA-IV is notable for its relatively specific expression in brain endothelial cells and the potency of AAVs that target it in mice. CA-IVs AAV binding site, and thus the mouse vectors enhanced brain potency, is not conserved across species, so we employed a two-phase engineering strategy to identify AAVs optimized for human CA-IV-dependent gene delivery to the brain. We first used in vitro receptor-based selection of a vast AAV library to exclude capsids that do not bind human CA-IV, followed by in vivo selection in "humanized" mice expressing human CA-IV in brain endothelial cells. Notably, we find that human CA-IV binding capsid variants that were poorly enriched in the pull-down selection outperform strong binders in vivo. The most promising vector, AAV-hCA4-IV77, engages human CA-IV to achieve 100-fold greater brain transduction than AAV9, with robust neuronal and astrocytic coverage throughout multiple brain regions. These results advance our understanding of receptor-targeted capsid design and support the therapeutic potential of human CA-IV-engaging AAVs.

bioengineering↗

bioRxiv2025

Sympathetic nociceptive afferent signaling drives the chronic structural and functional autonomic remodeling after myocardial infarction

After chronic myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, predisposes to ventricular arrhythmias (VT/VF). However, what underlies this functional and structural remodeling remains unknown. We hypothesized that sympathetic nociceptive afferent signaling initiates and perpetuates these pathological autonomic changes. We employ cervicothoracic epidural resiniferatoxin (RTX) to ablate spinal nociceptive neurons in male pigs before MI, and assessed autonomic and electrophysiological function four-to-six weeks post-infarction. Compared to vehicle-treated infarcted animals, epidural RTX attenuates the loss of vagal tone and baroreflex sensitivity, reduces spinal cord inflammation, glial activation, and circulating stress and inflammatory markers, and stabilizes electrophysiological parameters, lowering VT/VF inducibility. In a separate cohort, acute C7-T1 nociceptive afferent ablation after chronic MI acutely restores vagal function and decreases VT/VF inducibility. This study demonstrates that cervicothoracic spinal nociceptive afferents significantly contribute to MI-induced autonomic remodeling and VT/VF, providing novel insight into the mechanisms underlying sympathovagal imbalance after MI.

physiology↗

bioRxiv2024

The gut microbiome promotes mitochondrial respiration in the brain of a Parkinson's disease mouse model

The pathophysiology of Parkinsons disease (PD) involves gene-environment interactions that impair various cellular processes such as autophagy, lysosomal function, or mitochondrial dysfunction. Specifically, mitochondria-associated gene mutations increase PD risk, mitochondrial respiration is altered in the PD brain, and mitochondrial-damaging toxins cause PD-like motor and gastrointestinal symptoms in animal models. The gut microbiome is altered in PD patients and represents an environmental risk, however a relationship between mitochondrial function and the microbiome in PD has not been previously established. Herein, we report that striatal mitochondria are functionally overactive in -synuclein-overexpressing (ASO) mice, a model of PD, and that microbiome depletion restores respiration and mitochondria-associated gene expression patterns to wild-type levels. ASO mice harboring a complex microbiome produce increased reactive oxygen species in the striatum whereas germ-free counterparts express elevated levels of antioxidant proteins that may buffer against oxidative damage. Indeed, antioxidant treatment improves motor performance in ASO mice and, remarkably, blocking oxidant scavenging in germ-free mice induces -synuclein-dependent motor deficits. Thus, the gut microbiome increases mitochondrial respiration and oxidative stress in the brain, which enhances motor symptoms in a mouse model of PD.

physiology↗

bioRxiv2024

Thoracic epidural blockade after myocardial infarction benefits from anti-arrhythmic pathways mediated in part by parasympathetic modulation

BackgroundThoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachyarrhythmias (VT) in small case-series of patients with refractory VT and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear and its use after myocardial infarction (MI) is limited by concerns for potential RV dysfunction. MethodsMI was created in Yorkshire pigs (N=22) by LAD occlusion. Six weeks post-MI, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. RV and LV hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation-recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity (BRS) and intrinsic cardiac neural activity, and ventricular effective refractory periods (ERP) and slope of restitution (Smax) were assessed before and after TEA. VT/VF inducibility was assessed by programmed electrical stimulation. ResultsTEA reduced inducibility of VT/VF by 70%. TEA did not affect RV-systolic pressure or contractility, although LV-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular ERPs prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both BRS and intrinsic cardiac neural activity. ConclusionTEA does not compromise RV function in infarcted hearts. Its anti-arrhythmic mechanisms are mediated by increases in ventricular ERP and ARIs, decreases in Smax, and reductions in border zone heterogeneity. TEA improves parasympathetic function, which may independently underlie some of its observed anti-arrhythmic mechanisms. This study provides novel insights into the anti-arrhythmic mechanisms of TEA, while highlighting its applicability to the clinical setting. Abstract IllustrationMyocardial infarction is known to cause cardiac autonomic dysfunction characterized by sympathoexcitation coupled with reduced vagal tone. This pathological remodeling collectively predisposes to ventricular arrhythmia. Thoracic epidural anesthesia not only blocks central efferent sympathetic outflow, but by also blocking ascending projections of sympathetic afferents, relieving central inhibition of vagal function. These complementary autonomic effects of thoracic epidural anesthesia may thus restore autonomic balance, thereby improving ventricular electrical stability and suppressing arrhythmogenesis. DRG=dorsal root ganglion, SG=stellate ganglion. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/585127v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1150b29org.highwire.dtl.DTLVardef@8fd741org.highwire.dtl.DTLVardef@17d16bforg.highwire.dtl.DTLVardef@1608799_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗