Publications by authors named "Simon Waddington"
Recently approved adeno-associated viral (AAV) vectors for liver monogenic diseases haemophilia A and B are exemplifying the success of liver-directed viral gene therapy. In parallel, additional gene therapy strategies are rapidly emerging to overcome some inherent AAV limitations, such as the non-persistence of the episomal transgene in the rapidly growing liver and immune response. Viral integrating vectors such as in vivo lentiviral gene therapy and non-viral vectors such as lipid nanoparticles encapsulating mRNA (LNP-mRNA) are rapidly being developed, currently at the preclinical and clinical stages, respectively.
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- Researchers studied early-onset urinary tract disorders like urofacial syndrome (UFS), which is caused by a mutation affecting bladder function and can lead to kidney failure.
- Current treatments don't address the core issues of these disorders, prompting the exploration of a gene therapy approach using an adeno-associated viral (AAV9) vector to deliver the missing gene in neonatal mice.
- The treatment successfully expressed the missing protein in the pelvic ganglia and improved bladder function, suggesting that AAV9 gene therapy may offer a potential cure for UFS and related neurogenic bladder issues.
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- Parkinson's disease (PD) is a neurodegenerative condition linked to mutations in the LRRK2 gene, which plays a critical role in cellular signaling pathways related to brain function and immune development.
- The study aimed to explore how LRRK2 impacts Wnt and NFAT signaling in the brain, using genetically modified mice to observe signaling changes over 28 weeks.
- Results indicated that LRRK2 knockout mice showed a significant increase in Wnt signaling, especially in males, while NFAT signaling decreased in LRRK2 G2019S mutant mice, highlighting distinct regional effects in the brain.
Non-Ketotic Hyperglycinemia (NKH) is a rare inborn error of metabolism caused by impaired function of the glycine cleavage system (GCS) and characterised by accumulation of glycine in body fluids and tissues. NKH is an autosomal recessive condition and the majority of affected individuals carry mutations in GLDC (glycine decarboxylase). Current treatments for NKH have limited effect and are not curative.
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- - Gaucher Disease (GD) is a genetic disorder caused by mutations in the GBA1 gene and can result in severe brain and organ issues, particularly in the most serious infantile form known as neuronopathic GD (nGD), which currently has no cure.
- - This study tested AAV9 vectors delivering the human GBA1 gene at different doses, looking at both neuron-selective and broader promoters to see which worked best for treatment.
- - Findings suggest that using a neuron-targeted approach in gene therapy could maximize enzyme activity in the brain while minimizing effects elsewhere in the body, potentially leading to better treatment outcomes for nGD.
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- * Current strategies include gene therapies, with 38 clinical trials underway for pediatric metabolic disorders, and novel approaches for enhancing dopamine synthesis in Parkinson's disease.
- * Recent approvals, like the AAV2 gene therapy for AADC deficiency, show promise for treating these conditions, but the review highlights the need to consider various challenges in developing effective NT gene therapies.
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- - The enzyme argininosuccinate lyase (ASL) is crucial for processing ammonia and producing arginine; its deficiency leads to a metabolic disorder called argininosuccinic aciduria, causing heavy ammonia buildup, cognitive issues, and liver problems.
- - Researchers found that in ASL-deficient patients and mice, there is an imbalance in glutathione production and cysteine usage, leading to reduced antioxidant defense and worsening liver disease; they utilized PET imaging to non-invasively study these metabolic changes.
- - mRNA therapy improved glutathione levels and liver health in ASL-deficient mice, effectively correcting their metabolic issues, pointing to potential clinical applications for treating argininosuccinic aciduria through similar
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- Deafness impacts 5% of the global population, and current treatments for genetic hearing loss are largely lacking, particularly for disorders like Norrie disease, which is caused by mutations in the NDP gene and leads to dual sensory deprivation.
- Researchers utilized a Norrie disease mouse model to test a gene therapy approach, delivering the human NDP cDNA through an adeno-associated viral vector (AAV)9 at various developmental stages.
- Neonatal treatment showed promising results, preventing cochlear hair cell death and restoring both auditory function and retinal health, indicating potential for effective clinical therapy for Norrie disease-related hearing loss.
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- * Progress in the field now allows for earlier interventions in treating genetic diseases, with improved methods for diagnosing these conditions in utero.
- * The review covers the evolution of fetal gene therapy, advancements in fetal surgery and diagnosis, and examines ongoing research in gene therapy aimed at inherited metabolic diseases.
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- Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is a rare childhood movement disorder caused by mutations in a specific gene affecting dopamine transport.
- Since it was first characterized in 2009, 31 cases have been documented, showing various genetic mutations that lead to malfunctioning dopamine transporters.
- The review discusses the diverse symptoms of DTDS and highlights potential precision therapies under development, such as pharmacochaperones and gene therapy.
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- - Neurological disorders are a diverse group of diseases with significant unmet needs for effective treatments; current options largely lack disease-modifying therapies.
- - Viral gene therapies, particularly using vectors like adeno-associated virus and lentivirus, have shown promising results in pediatric conditions like spinal muscular atrophy and AADC deficiency, changing the disease's trajectory.
- - Recent advancements in gene therapy are focused on Parkinson's disease and related neurotransmitter disorders, but challenges remain, including identifying the best treatment window and ensuring effective brain targeting.
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- Over 1,000 unexplained pediatric hepatitis cases have been identified globally, with a study focusing on 38 cases and various control groups to understand potential viral causes.
- High levels of adeno-associated virus 2 (AAV2) DNA were found in most cases, while low levels of adenovirus and human herpesvirus 6B were also detected; however, AAV2 appeared infrequently in healthy controls even when they were immunocompromised.
- The study suggests that abnormal replication of AAV2, potentially influenced by other viruses like HAdV and HHV-6B, may be responsible for immune-related liver disease in susceptible children.
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- Adeno-associated viral vectors (AAVs) are important for gene therapy due to their efficiency and safety, but making them in large amounts is still a challenge.
- This study introduces nanogels created using microfluidics as a cost-effective alternative to common reagents like polyethylenimine-MAX (PEI-MAX) for producing AAV vectors, achieving similar yields.
- The experiments showed that nanogels can produce high yields of AAV vectors, with optimized formulations leading to comparable results to PEI-MAX, indicating a promising method for more efficient and affordable gene therapy production.
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- Lentiviral vectors (LV) are promising tools for gene therapy, but can lead to insertional mutagenesis, making it crucial to study their integration into host genomes.
- The research focuses on how transcription factors (TF) may influence the process of LV integration by mapping predicted binding sites near the insertion points chosen by HIV-1 LV in human induced pluripotent stem cells and their derivatives.
- Findings indicate that specific transcription factor binding sites (pTFBS) are enriched in the LV insertion sites and are essential for the HIV-1 life cycle, suggesting their importance in viral survival and propagation.
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- * Traditional treatments, including ammonia scavengers and liver transplants, have risks and limitations, prompting interest in new gene therapies using adeno-associated viral (AAV) vectors.
- * A study using juvenile monkeys showed that a liver-targeted AAV gene therapy (AAVLK03) was safe, well-tolerated, and effectively increased OTC levels, supporting its potential for treating severe OTCD in humans.
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- * Traditional cell lysates require purification methods, like caesium chloride or chromatography, but have limitations such as poor infectiousness and restricted storage capability.
- * An innovative aqueous two-phase system (ATPS) using 20% PEG 600 and 20% (NH)SO has been shown to efficiently purify AdVs, yielding over 97% high-titre virus with no cytotoxic effects, and stable storage at -20 °C or 4 °C for future clinical
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- The human adenovirus family is divided into seven species, with species D showing promise for gene therapy due to low pre-existing immunity in the population.
- Human adenovirus type 49 (HAdV-D49) was studied and found to utilize multiple pathways for cell entry, allowing it to infect a variety of cell types.
- HAdV-D49 demonstrates reduced targeting of the liver compared to adenovirus type 5, making it a potentially effective vector for targeting the lung and spleen while minimizing liver interactions, which is beneficial for vaccine delivery.
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- Most neurodegenerative disorders lack cures, but precision medicine offers promising avenues for treatment, particularly for dopamine transporter deficiency syndrome (DTDS), which is tied to mutations in the dopamine transporter gene.
- Researchers created a dopaminergic neuron model from patient-derived induced pluripotent stem cells (iPSCs) to study DTDS and found that a pharmacochaperone could partially restore dopamine transporter activity, while gene therapy showed more comprehensive benefits.
- Testing in a knockout mouse model of DTDS demonstrated that targeted adeno-associated virus (AAV) gene therapy could significantly improve motor function and neuron survival, highlighting its potential for clinical application in treating DTDS.
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- Rare monogenic disorders, like lysosomal diseases, often lack effective treatments, making the development of new therapies crucial.
- Recent advancements in gene therapy have shown promise, with numerous successful studies indicating its potential to meet the healthcare needs of affected patients.
- The article reviews popular viral vectors used for gene delivery and summarizes significant pre-clinical studies and ongoing clinical trials related to lysosomal storage disorders.
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- Lentiviral vectors derived from HIV-1 usually integrate their RNA genome into the host cell's DNA, leading to long-lasting gene expression, but integration-deficient versions have been created to minimize this persistence.
- New research focuses on optimizing a reverse-transcriptase-deficient lentiviral vector that allows for the direct translation of RNA genomes in cells, bypassing the need for a DNA step.
- This innovative LV design promotes efficient expression of genetic material without integration, making it promising for temporary gene expression in gene and cell therapy applications.
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- Urea cycle disorders (UCD) are genetic conditions that hinder the body’s ability to remove waste nitrogen, leading to serious health issues.
- Research identified Beclin-1 as a promising target for treatment, and the peptide Tat-Beclin-1 (TB-1) was tested for its effectiveness in common UCD types.
- TB-1 showed beneficial effects in animal models, reducing harmful substances, enhancing survival rates on high-protein diets, and improving liver health in both types of UCD.
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- An amendment to the original paper has been published.
- Readers can find the amendment through a link provided at the top of the paper.
- This update likely contains important revisions or additional information regarding the original content.
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- - Approximately 40% of preterm births are linked to infections that spread from the vagina to the uterus, highlighting the importance of cervical defense mechanisms against such infections.
- - Researchers tested the effect of a specific antimicrobial peptide, human β-defensin-3 (HBD3), delivered via a virus vector in pregnant mice to prevent bacterial infections.
- - Results showed that mice treated with HBD3 had less bacterial growth in the uterus and a higher number of live pups, suggesting HBD3 could enhance cervical immunity and reduce the risk of preterm birth.
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- - The study enhances previously developed lentiviral vector technology by utilizing adeno-associated viral vectors (AAV) to generate transgenic rodents for monitoring disease-related signaling pathways through non-invasive whole-body bioluminescence imaging.
- - After administering AAV8 intravenously, researchers observed widespread expression of genes (GFP and luciferase) in various organs, demonstrating a strong and lasting luciferase expression lasting up to 240 days.
- - The research validated a new biosensor that employs an NFκB response element, which can effectively track signaling pathways in rodents during inflammation, offering potential advancement in studying various rodent disease models.