Objective
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons, resulting in progressive muscle weakness, paralysis, and death within 5 ...years of diagnosis. About 10% of cases are inherited, of which 20% are due to mutations in the superoxide dismutase 1 (SOD1) gene. Riluzole, the only US Food and Drug Administration–approved ALS drug, prolongs survival by only a few months. Experiments in transgenic ALS mouse models have shown decreasing levels of mutant SOD1 protein as a potential therapeutic approach. We sought to develop an efficient adeno‐associated virus (AAV)‐mediated RNAi gene therapy for ALS.
Methods
A single‐stranded AAV9 vector encoding an artificial microRNA against human SOD1 was injected into the cerebral lateral ventricles of neonatal SOD1G93A mice, and impact on disease progression and survival was assessed.
Results
This therapy extended median survival by 50% and delayed hindlimb paralysis, with animals remaining ambulatory until the humane endpoint, which was due to rapid body weight loss. AAV9‐treated SOD1G93A mice showed reduction of mutant human SOD1 mRNA levels in upper and lower motor neurons and significant improvements in multiple parameters including the numbers of spinal motor neurons, diameter of ventral root axons, and extent of neuroinflammation in the SOD1G93A spinal cord. Mice also showed previously unexplored changes in pulmonary function, with AAV9‐treated SOD1G93A mice displaying a phenotype reminiscent of patient pathophysiology.
Interpretation
These studies clearly demonstrate that an AAV9‐delivered SOD1‐specific artificial microRNA is an effective and translatable therapeutic approach for ALS. Ann Neurol 2016;79:687–700
Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation ...in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide‐crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.
Synopsis
Dysregulation of endoplasmic reticulum (ER) proteostasis is associated with various neurological problems. Here, study of patients with homozygous mutation in PDIA3 links disturbed proteostasis in intellectual disability directly to effects on neuronal connectivity and function.
A homozygous mutation disrupting a redox motif of protein disulfide isomerase A3 (PDIA3) is identified as a possible cause of syndromic intellectual disability.
Pathogenic features associated with mutant PDIA3 include reduced enzymatic activity, formation of protein aggregates, and abnormal interaction with ER chaperones.
Impaired ER proteostasis due to mutant PDIA3 expression results in altered biogenesis of secretory pathway cargoes including integrins, key adhesion molecules involved in synaptic function and plasticity.
Mutant PDIA3 alters neuronal morphogenesis and connectivity, impairing cognitive function such as memory consolidation.
Study of a rare intellectual disability‐linked variant in ER enzyme PDIA3 links cellular proteostasis defects directly to cytoskeleton and adhesion pathways required for neuronal morphogenesis and connectivity.
The GREGOR telescope was inaugurated in 2012. In 2018, we began a complete upgrade, involving optics, alignment, instrumentation, mechanical upgrades for vibration reduction, updated control systems, ...and building enhancements, and in addition, adapted management and policies. This paper describes all major updates performed during this time. Since 2012, all powered mirrors except for M1 were exchanged. Since March 2020, GREGOR observes with diffraction-limited performance and a new optics and instrument layout.
The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard‐of‐care treatment and thus a direct cause of ...death. Previously, we have shown that intracranial interferon‐beta (IFN‐β) gene therapy by locally administered adeno‐associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN‐β eliminates invasive human GBM8 tumors and promotes long‐term survival. Next, we screened five AAV‐IFN‐β vectors with different promoters to drive safe expression of mouse IFN‐β in the brain in the context of syngeneic GL261 tumors. Two AAV‐IFN‐β vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2‐Int‐mIFN‐β vector. We also assessed the therapeutic effect of combining AAV‐IFN‐β therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second‐strand DNA synthesis of single‐stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV‐IFN‐β abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV‐IFN‐β therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency.
Our study shows that species‐matched interferon‐beta (IFN‐β) gene therapy by locally administered adeno‐associated viral vectors (AAV) is an effective therapeutic approach for treating both highly invasive human glioblastoma and syngeneic mouse glioblastoma in mouse orthotopic models. We also show that combination treatment with AAV‐IFN‐β and temozolomide (TMZ) provides enhanced therapeutic benefit if AAV‐IFN‐β is administered prior to TMZ.
Intimate partner violence (IPV) is global public health issue and refers to the violence committed by a partner in the context of an intimate relationship, regardless of whether or not it is legally ...recognized. This review aims to analyze the personality characteristics present in victims of IPV, addressing the causes and consequences of the abusive relationship. Studies focusing on female victims were obtained through multiple databases, following the Cochrane Collaboration procedures. Of the 87 documents collected, 31 were retained for further analysis and considered eligible for inclusion, with ten studies from manual search being included. The objectives, methodological aspects (sample/instruments), and main conclusions were extracted from each study. The results suggest that women tend to become victims when they experience violence during childhood, when they are economically dependent, lack social support, and fear for their lives. The consequences consist of physical and psychological sequelae that remain throughout life. There are personality traits that make the victim susceptible to remaining in an abusive relationship. Women who have experienced IPV obtained higher scores in schizoid, avoidant, self-destructive, schizotypal, borderline, and paranoid personality scales. Therefore, female victims exhibit characteristics such as low personal self-esteem, family and social isolation, dependency (economic and emotional), insecurity, inferiority, submissiveness, and pacification. This review is particularly useful for clinical practice and intervention with victims of IPV, by bringing to light specific personality traits, cognitive schemas and/or possible diagnoses that are most common among these victims and make them more vulnerable to remaining in abusive relationships.
Objective
GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay‐Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, ...and children succumb to the disease after a protracted neurodegenerative course and semi‐vegetative state. This study seeks to further develop adeno‐associated virus (AAV) gene therapy for human translation.
Methods
Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline β‐N‐acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis.
Results
Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4 ± 0.6 months, AAV‐treated cats lived to 19.1 ± 8.6 months, and 3 of 9 cats lived >21 months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated.
Interpretation
The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole‐body targeting will be an important consideration in next‐generation approaches. ANN NEUROL 2023;94:969–986
Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment ...approaches – pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others – have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors – encoding a therapeutic gene or inhibitory RNA into a “gutted” viral capsid and supplying it to the nervous system – has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future.
This article is part of the Special Issue entitled “Beyond small molecules for neurological disorders”.
•Provides an overview of viral vector-mediated gene therapy for brain disorders.•Greater, safer genetic access to the central nervous system by viral vector tools.•Focus on clinical progress for neurological disorders and brain tumors.•Outline of existing challenges and future directions for clinical gene therapy.
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•New modular metal pallets that combine blocks and deck boards are proposed.•3D FEM, analytical, and experimental tests are carried out and results compared.•More reliable values for ...loadings and displacements are provided for steel pallets.•A comparative LCA suggests that steel pallets have a good environmental performance.
Given the huge number of products transported worldwide every day, it would be advantageous to use lightweight pallets made of readily recyclable materials that are easy to clean, durable, and cheap to maintain. However, the design process for new metal pallets does not follow any specific code, which makes the transition to products with improved characteristics more challenging. This paper describes the development of a new modular steel pallet that combines blocks and deck boards to produce a range of configurable geometries for use in transportation (forklifting) and stationary (racking, stacking) conditions alike. Analytical and numerical analyses using the 3D finite element method (FEM) were carried out. Experimental tests were performed to evaluate ultimate strengths and deformations for different loadings. The experimental results used to validate the numerical models showed that these pallets performed well in terms of stiffness, deformation, and stresses. A comparative life cycle analysis (LCA) was also carried out to identify the main environmental impacts of the life cycle of pallets made from different materials. The results of a “cradle-to-gate with options” model suggest that the new proposed pallet performs better than its wood, plastic, and aluminium counterparts.
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