VAL-1221 for the treatment of patients with Lafora disease: study protocol for a single-arm, open-label clinical trial.

Introduction: Lafora disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the accumulation of polyglucosans in the brain and neurodegeneration. There are no approved treatments for LD.

Poor Reliability of Common Measures of Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation.

Anticoagulation management in pediatric extracorporeal membrane oxygenation (ECMO) is challenging with multiple laboratory measures utilized across institutions without consensus guidelines. These include partial thromboplastin time (PTT), thromboelastography (TEG), and antifactor Xa (aXa). We aimed to evaluate the consistency of TEG R-time, PTT, and aXa correlation to bivalirudin and heparin dosing.

The interaction of anti-DNA antibodies with DNA antigen: Evidence for hysteresis for high avidity binding.

Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus. Previous studies have indicated that the phosphodiester backbone is the main antigenic target, with electrostatic interactions important for high avidity. To define further these interactions, the effects of ionic strength on anti-DNA binding of SLE plasmas were assessed in association and dissociation assays by ELISA.

Brain glycogen serves as a critical glucosamine cache required for protein glycosylation.

Glycosylation defects are a hallmark of many nervous system diseases. However, the molecular and metabolic basis for this pathology is not fully understood. In this study, we found that N-linked protein glycosylation in the brain is metabolically channeled to glucosamine metabolism through glycogenolysis.

The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic.

Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain.

Antibody-Mediated Enzyme Therapeutics and Applications in Glycogen Storage Diseases.

The use of antibodies as targeting molecules or cell-penetrating tools has emerged at the forefront of pharmaceutical research. Antibody-directed therapies in the form of antibody-drug conjugates, immune modulators, and antibody-directed enzyme prodrugs have been most extensively utilized as hematological, rheumatological, and oncological therapies, but recent developments are identifying additional applications of antibody-mediated delivery systems. A novel application of this technology is for the treatment of glycogen storage disorders (GSDs) via an antibody-enzyme fusion (AEF) platform to penetrate cells and deliver an enzyme to the cytoplasm, nucleus, and/or other organelles.

Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease.

Lafora disease (LD) is a fatal juvenile epilepsy characterized by the accumulation of aberrant glucan aggregates called Lafora bodies (LBs). Delivery of protein-based therapeutics to the central nervous system (CNS) for the clearance of LBs remains a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and proposed as a broadly applicable carrier to mediate cellular targeting and uptake.

Antibody-mediated enzyme replacement therapy targeting both lysosomal and cytoplasmic glycogen in Pompe disease.

Unlabelled: Pompe disease is characterized by accumulation of both lysosomal and cytoplasmic glycogen primarily in skeletal and cardiac muscles. Mannose-6-phosphate receptor-mediated enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) targets the enzyme to lysosomes and thus is unable to digest cytoplasmic glycogen. Studies have shown that anti-DNA antibody 3E10 penetrates living cells and delivers "cargo" proteins to the cytosol or nucleus via equilibrative nucleoside transporter ENT2.

Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy.

No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1δ4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency.

Expression of beta-catenin is necessary for physiological growth of adult skeletal muscle.

Expression of beta-catenin is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Inappropriate expression, however, has been linked to pathological states such as cancer. Here we report that expression of beta-catenin is necessary for physiological growth of skeletal muscle in response to mechanical overload.

Wnt/beta-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy.

Beta-catenin is a transcriptional activator shown to regulate the embryonic, postnatal, and oncogenic growth of many tissues. In most research to date, beta-catenin activation has been the unique downstream function of the Wnt signaling pathway. However, in the heart, a Wnt-independent mechanism involving Akt-mediated phosphorylation of glycogen synthase kinase (GSK)-3beta was recently shown to activate beta-catenin and regulate cardiomyocyte growth.

Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch: implications for mechanotransduction.

Several lines of evidence suggest that muscle cells can distinguish between specific mechanical stimuli. To test this concept, we subjected C(2)C(12) myotubes to cyclic uniaxial or multiaxial stretch. Both types of stretch induced an increase in extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/Akt) phosphorylation, but only multiaxial stretch induced ribosomal S6 kinase (p70(S6k)) phosphorylation.

Selenoprotein-deficient transgenic mice exhibit enhanced exercise-induced muscle growth.

Dietary intake of selenium has been implicated in a wide range of health issues, including aging, heart disease and cancer. Selenium deficiency, which can reduce selenoprotein levels, has been associated with several striated muscle pathologies. To investigate the role of selenoproteins in skeletal muscle biology, we used a transgenic mouse (referred to as i6A-) that has reduced levels of selenoproteins due to the introduction and expression of a dominantly acting mutant form of selenocysteine transfer RNA (tRNA[Ser]Sec).