Absence of lenadogene nolparvovec DNA in a brain tumor biopsy from a patient in the REVERSE clinical study, a case report.

Background: Leber Hereditary Optic Neuropathy (LHON) is a rare, maternally-inherited mitochondrial disease that primarily affects retinal ganglion cells (RGCs) and their axons in the optic nerve, leading to irreversible, bilateral severe vision loss. Lenadogene nolparvovec gene therapy was developed as a treatment for patients with vision loss from LHON caused by the most prevalent m.11778G > A mitochondrial DNA point mutation in the MT-ND4 gene.

Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.

Drugs that block voltage-gated sodium channels (Nas) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther.

Neurological perspectives on voltage-gated sodium channels.

The activity of voltage-gated sodium channels has long been linked to disorders of neuronal excitability such as epilepsy and chronic pain. Recent genetic studies have now expanded the role of sodium channels in health and disease, to include autism, migraine, multiple sclerosis, cancer as well as muscle and immune system disorders. Transgenic mouse models have proved useful in understanding the physiological role of individual sodium channels, and there has been significant progress in the development of subtype selective inhibitors of sodium channels.

TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells.

Transient receptor potential (TRP) channels TRPC3 and TRPC6 are expressed in both sensory neurons and cochlear hair cells. Deletion of TRPC3 or TRPC6 in mice caused no behavioural phenotype, although loss of TRPC3 caused a shift of rapidly adapting (RA) mechanosensitive currents to intermediate-adapting currents in dorsal root ganglion sensory neurons. Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents.

Sodium channels and mammalian sensory mechanotransduction.

Background: Members of the degenerin/epithelial (DEG/ENaC) sodium channel family are mechanosensors in C elegans, and Nav1.7 and Nav1.8 voltage-gated sodium channel knockout mice have major deficits in mechanosensation.

Pain channelopathies.

Pain remains a major clinical challenge, severely afflicting around 6% of the population at any one time. Channelopathies that underlie monogenic human pain syndromes are of great clinical relevance, as cell surface ion channels are tractable drug targets. The recent discovery that loss-of-function mutations in the sodium channel Nav1.

Kinetic properties of mechanically activated currents in spinal sensory neurons.

Dorsal root ganglion neurons in vitro express a number of types of mechanically activated currents that are thought to underlie somatic mechanosensory transduction in vivo. We have studied the inactivation properties of these currents to assess how they might influence the electrophysiological responses of dorsal root ganglion (DRG) neurons to mechanical stimulation. We show that the speed of ramp-like mechanical stimulation determines the dynamics of mechanically activated current responses and hence the type of DRG neuron most likely to be activated.

A multi PDZ-domain protein Pdzd2 contributes to functional expression of sensory neuron-specific sodium channel Na(V)1.8.

The voltage-gated sodium channel Na(V)1.8 is expressed exclusively in nociceptive sensory neurons and plays an important role in pain pathways. Na(V)1.

The mechanosensitive cell line ND-C does not express functional thermoTRP channels.

The molecular basis of mechanosensation in sensory neurons has yet to be defined. We found that ND-C cells, a hybrid cell line derived from neonatal rat DRG neurons, express mechanosensitive ion channels, and provide a useful expression system for testing candidate mechanosensitive ion channels. ND-C cells retain some important features of DRG neurons such as the expression of TTX-sensitive Na(+) and acid-activated currents as well as the ability to respond to mechanical stimulation with cationic currents sensitive to the analgesic peptide NMB1.

Regulation of ASIC activity by ASIC4--new insights into ASIC channel function revealed by a yeast two-hybrid assay.

ASIC4 is a member of the acid-sensing ion channel family that is broadly expressed in the mammalian nervous system, but has no known function. We demonstrate here that transfected ASIC4 is targeted to the plasma membrane in CHO-K1 cells, where it associates with ASIC1a and downregulates exogenous ASIC1a expression. This effect could also be observed on endogenous H+-gated currents in TSA-201 cells and ASIC3 currents in CHO-K1 cells, suggesting a physiological role for ASIC4 in regulating ASIC currents involved in pain mechanisms.

High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain.

Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC(50) 1 microM) sustained mechanically activated currents in a subset of sensory neurons.

Touch.

Light touch, a sense of muscle position, and the responses to tissue-damaging levels of pressure all involve mechanosensitive sensory neurons that originate in the dorsal root or trigeminal ganglia. A variety of mechanisms of mechanotransduction are proposed. These ranges from direct activation of mechanically activated channels at the tips of sensory neurons to indirect effects of intracellular mediators, or chemical signals released from distended tissues, or specialized mechanosensory end organs.

Annexin II light chain p11 promotes functional expression of acid-sensing ion channel ASIC1a.

Acid-sensing ion channels (ASICs) have been implicated in a wide variety of physiological functions. We have used a rat dorsal root ganglion cDNA library in a yeast two-hybrid assay to identify sensory neuron proteins that interact with ASICs. We found that annexin II light chain p11 physically interacts with the N terminus of ASIC1a, but not other ASIC isoforms.

Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons.

Voltage-gated Na(+) currents play critical roles in shaping electrogenesis in neurons. Here, we have identified a TTX-resistant Na(+) current (TTX-R I(Na)) in duodenum myenteric neurons of guinea pig and rat and have sought evidence regarding the molecular identity of the channel producing this current from the expression of Na(+) channel alpha subunits and the biophysical and pharmacological properties of TTX-R I(Na). Whole-cell patch-clamp recording from in situ neurons revealed the presence of a voltage-gated Na(+) current that was highly resistant to TTX (IC(50), approximately 200 microm) and selectively distributed in myenteric sensory neurons but not in interneurons and motor neurons.

Analysis of whole-cell currents by patch clamp of guinea-pig myenteric neurones in intact ganglia.

Whole-cell patch-clamp recordings taken from guinea-pig duodenal myenteric neurones within intact ganglia were used to determine the properties of S and AH neurones. Major currents that determine the states of AH neurones were identified and quantified. S neurones had resting potentials of -47 +/- 6 mV and input resistances (R(in)) of 713 +/- 49 MOmega at voltages ranging from -90 to -40 mV.