Binding and neutralizing anti-AAV antibodies: Detection and implications for rAAV-mediated gene therapy.

Assessment of anti-adeno-associated virus (AAV) antibodies in patients prior to systemic gene therapy administration is an important consideration regarding efficacy and safety of the therapy. Approximately 30%-60% of individuals have pre-existing anti-AAV antibodies. Seroprevalence is impacted by multiple factors, including geography, age, capsid serotype, and assay type.

Durability of transgene expression after rAAV gene therapy.

Recombinant adeno-associated virus (rAAV) gene therapy has the potential to transform the lives of patients with certain genetic disorders by increasing or restoring function to affected tissues. Following the initial establishment of transgene expression, it is unknown how long the therapeutic effect will last, although animal and emerging human data show that expression can be maintained for more than 10 years. The durability of therapeutic response is key to long-term treatment success, especially since immune responses to rAAV vectors may prevent re-dosing with the same therapy.

A Retrospective Study of Clinical and Economic Burden of Focal Segmental Glomerulosclerosis (FSGS) in the United States.

Introduction: Information on the economic burden of focal segmental glomerulosclerosis (FSGS) is sparse. This study characterized health care resource utilization (HCRU) and costs in patients with FSGS, and evaluated the impact of nephrotic range proteinuria on these outcomes.

Methods: This retrospective, observational cohort study used administrative claims data from the Optum Clinformatics Data Mart Database from October 2015 to December 2019.

PODO: Trial Design: Phase 2 Study of PF-06730512 in Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS) is characterized by proteinuria and a histologic pattern of glomerular lesions of diverse etiology that share features including glomerular scarring and podocyte foot process effacement. Roundabout guidance receptor 2 (ROBO2)/slit guidance ligand 2 (SLIT2) signaling destabilizes the slit diaphragm and reduces podocyte adhesion to the glomerular basement membrane (GBM). Preclinical studies suggest that inhibition of glomerular ROBO2/SLIT2 signaling can stabilize podocyte adhesion and reduce proteinuria.

Incremental health care resource utilization and expenditures associated with autosomal-dominant polycystic kidney disease.

Purpose: Incremental health care resource utilization and expenditures associated with autosomal dominant polycystic kidney disease (ADPKD) were estimated.

Methods: Study data were from a large administrative claims database. Individuals aged 18 years or older enrolled in tracked health plans for 12 months from April 1, 2011 through March 31, 2012, and with an International Classification of Disease, Ninth Revision, Clinical Modification diagnosis code for "polycystic kidney, autosomal dominant" (753.

Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice.

Myocardial repolarization capacity varies with sex, age, and pathology; the molecular basis for this variation is incompletely understood. Here, we show that the transcript for KCNE4, a voltage-gated potassium (Kv) channel β subunit associated with human atrial fibrillation, was 8-fold more highly expressed in the male left ventricle compared with females in young adult C57BL/6 mice (P < 0.05).

Long-term evaluation of analytical methods used in sirolimus therapeutic drug monitoring.

Results of therapeutic monitoring of sirolimus blood concentrations are assay and laboratory dependent. This study compared performance over time of the IMx microparticle enzyme immunoassay (MEIA), Architect chemiluminescent microparticle immunoassay (CMIA), and liquid chromatography with mass spectrometric detection (LC/MS/MS) as part of a proficiency testing scheme. Pooled samples from sirolimus-treated patients and whole-blood samples spiked with known quantities of sirolimus were assayed monthly between 2004 and 2012.

The membrane protein MiRP3 regulates Kv4.2 channels in a KChIP-dependent manner.

MiRP3, the single-span membrane protein encoded by KCNE4, is localized by immunofluorescence microscopy to the transverse tubules of murine cardiac myocytes. MiRP3 is found to co-localize with Kv4.2 subunits that contribute to cardiac transient outward potassium currents (I(to)).

MiRP3 acts as an accessory subunit with the BK potassium channel.

MinK-related peptides (MiRPs) are single-span membrane proteins that assemble with specific voltage-gated K+ (Kv) channel alpha-subunits to establish gating kinetics, unitary conductance, expression level, and pharmacology of the mixed complex. MiRP3 (encoded by the KCNE4 gene) has been shown to alter the behavior of some Kv alpha-subunits in vitro but its natural partners and physiologic functions are unknown. Seeking in vivo partners for MiRP3, immunohistochemistry was used to localize its expression to a unique subcellular site, the apical membrane of renal intercalated cells, where one potassium channel type has been recorded, the calcium- and voltage-gated channel BK.

pH-dependent modulation of Kv1.3 inactivation: role of His399.

The Kv1.3 K(+) channel lacks N-type inactivation, but during prolonged depolarized periods it inactivates via the slow (P/C type) mechanism. It bears a titratable histidine residue in position 399 (equivalent of Shaker 449), a site known to influence the rate of slow inactivation.

Functional polymorphism in the carboxyl terminus of the alpha-subunit of the human epithelial sodium channel.

A common human epithelial sodium channel (ENaC) polymorphism, alphaT663A, is present in the cytoplasmic C terminus of the alpha-subunit, although it is unclear whether this polymorphism segregates with blood pressure. We examined whether this polymorphism was associated with differences in functional Na(+) channel expression. Whole cell amiloride-sensitive currents in Xenopus oocytes expressing wild type channels (alphaT663betagamma) were significantly approximately 1.

Segment-specific expression of 2P domain potassium channel genes in human nephron.

Background: The 2P domain potassium (K2P) channels are a recently discovered ion channel superfamily. Structurally, K2P channels are distinguished by the presence of two pore forming loops within one channel subunit. Functionally, they are characterized by their ability to pass potassium across the physiologic voltage range.