A5053691264- Virus-based gene therapy research
- Metabolism and Genetic Disorders
- RNA Interference and Gene Delivery
- Liver physiology and pathology
- Mitochondrial Function and Pathology
- CRISPR and Genetic Engineering
- Neonatal Respiratory Health Research
- bioluminescence and chemiluminescence research
- Viral gastroenteritis research and epidemiology
- Immune Cell Function and Interaction
- Immune Response and Inflammation
- Amino Acid Enzymes and Metabolism
- Preterm Birth and Chorioamnionitis
- Pancreatic function and diabetes
- Autophagy in Disease and Therapy
- Tissue Engineering and Regenerative Medicine
- Anesthesia and Neurotoxicity Research
- Immune cells in cancer
- Lysosomal Storage Disorders Research
- Cancer, Hypoxia, and Metabolism
- Muscle Physiology and Disorders
- Extracellular vesicles in disease
- CAR-T cell therapy research
- Animal Genetics and Reproduction
- Pediatric Hepatobiliary Diseases and Treatments
University College London
2015-2024
Great Ormond Street Hospital
2018-2024
Great Ormond Street Hospital for Children NHS Foundation Trust
2022-2023
University of Oxford
2013-2021
University College Lahore
2018
Nuffield Orthopaedic Centre
2017
London Women's Clinic
2015
Imperial College London
2010
The most studied biological role of type III interferons (IFNs) has so far been their antiviral activity, but in autoimmune and inflammatory diseases remains largely unexplored. Here, we show that treatment with IFN-λ2/IL-28A completely halts reverses the development collagen-induced arthritis (CIA) discover cellular molecular mechanisms IL-28A antiinflammatory function. We demonstrate dramatically reduces numbers proinflammatory IL-17–producing Th17 γδ T cells joints inguinal lymph nodes,...
The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and biosynthesis arginine. Patients with ASL deficiency present argininosuccinic aciduria, an inherited metabolic disease hyperammonemia a systemic phenotype coinciding neurocognitive impairment chronic liver disease. Here, we describe dysregulation glutathione upstream cysteine utilization in ASL-deficient patients mice using targeted metabolomics vivo positron emission tomography (PET) imaging (...
Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there an increasing awareness that neutrophils may also play important role. In addition to well-documented heterogeneity macrophage phenotypes and functions, show remarkable phenotypic diversity among tissues. Understanding molecular pathways control this should provide abundant scope for generation more specific effective therapeutics. We have shown transcription factor IFN regulatory 5 (IRF5)...
Type 4 phosphodiesterases (PDE4) play an important role in immune cells through the hydrolysis of second messenger, cAMP. Inhibition PDE4 has previously been shown to suppress and inflammatory responses, demonstrating be a valid therapeutic target for immune-mediated pathologies. We assessed anti-inflammatory effects novel inhibitor, apremilast, human synovial from rheumatoid arthritis (RA) patients, as well two murine models arthritis.Cells liberated tissue excised arthritic joints RA...
Macrophages are an integral part of the innate immune system and key players in pathogen clearance tissue remodelling. Both functions accomplished by a pivotal network different macrophage subtypes, including proinflammatory M1 anti-inflammatory M2 macrophages. Previously, our laboratory identified transcription factor interferon regulatory 5 (IRF5) as master regulator polarisation. IRF5 was found to be highly expressed human compared Furthermore, dictates expression genes such IL12b IL23a...
Objective Tumor necrosis factor (TNF) signals via 2 receptors, TNFR type I (TNFRI) and TNFRII, with distinct cellular distribution signaling functions. In rheumatoid arthritis (RA), the net effect of favors inflammatory responses while inhibiting activity regulatory T cells. TNFRII has been shown to promote Treg cell function. To assess relative contributions TNFRI in vivo, we compared TNF blockade, hence TNFRI/II, versus alone collagen‐induced (CIA) as a model RA. Methods Mice established...
Significance TNF signals via 2 receptors, TNFR1 and TNFR2. Anti-TNF biologics, which block signaling both are now being used to treat millions of patients worldwide for immune-mediated inflammatory diseases. This study demonstrates that TNFR2 plays a major role in limiting the severity duration arthritis animal models is important maintaining functional activity phenotypic stability Treg cells, cellular mediators immune homeostasis. cells express functionally transcription factor FoxP3, we...
Recombinant adeno-associated virus (rAAV) vectors are a promising platform for in vivo gene therapy. The presence of neutralizing antibodies (Nab) against AAV capsids decreases cell transduction efficiency and is common exclusion criterion participation clinical trials. Novel engineered being generated to improve delivery the target cells facilitate success trials; however, prevalence such remains largely unknown. We therefore assessed seroprevalence novel synthetic liver-tropic capsid...
Preterm birth is a serious global health problem and the leading cause of infant death before 5 years age. At least 40% cases are associated with infection. The most common way for pathogens to access uterine cavity by ascending from vagina. Bioluminescent have revolutionized understanding infectious diseases. We hypothesized that bioluminescent Escherichia coli can be used track monitor vaginal infections. Two strains were studied: E. K12 MG1655-lux, nonpathogenic laboratory strain, K1...
Viral vectors restore dopamine transporter function and ameliorate neuropathology in iPSC-derived neurons a mouse model of infantile parkinsonism.
The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors. Multiple clinical trials have been undertaken this the past 15 years; however, we are still to see market approval of first liver-targeted virus (AAV)-based therapy. Inefficient expression therapeutic transgene, vector-induced toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses main challenges date. One contributing factors insufficient outcomes,...
Abstract The application of transcription factor activated luciferase reporter cassettes in vitro is widespread but potential for vivo has not yet been realized. Bioluminescence imaging enables non-invasive tracking gene expression transfected tissues living rodents. However the mature immune response limits when delivered adulthood. We present a novel approach tissue-targeted delivery lentiviruses to neonatal rodents as an alternative existing technology generating germline transgenic light...
Abstract Argininosuccinate lyase (ASL) belongs to the hepatic urea cycle detoxifying ammonia, and citrulline-nitric oxide (NO) producing NO. ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia, multiorgan disease neurocognitive impairment despite treatment aiming normalise ammonaemia without considering NO imbalance. Here we show that cerebral in involves neuronal oxidative/nitrosative stress independent of hyperammonaemia. Intravenous injection AAV8...
X-linked inherited ornithine transcarbamylase deficiency (OTCD) is the most common disorder affecting liver-based urea cycle, a pathway enabling detoxification of nitrogen waste and endogenous arginine biosynthesis. Patients develop acute hyperammonemia leading to neurological sequelae or death despite best-accepted therapy based on ammonia scavengers protein-restricted diet. Liver transplantation curative but associated with procedure-related complications lifelong immunosuppression....
<ns3:p>Background In academic research and the pharmaceutical industry, <ns3:italic>in vitro</ns3:italic> cell lines vivo</ns3:italic> animal models are considered as gold standards in modelling diseases assessing therapeutic efficacy. However, both have intrinsic limitations, whilst use of precision-cut tissue slices can bridge gap between these mainstream models. Precision-cut combine advantage high reproducibility, studying all sub-types preserving matrix extracellular architecture,...
Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent major genetic risk for Parkinson's disease (PD), while homozygous GBA1 cause Gaucher disease, a storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways mitochondrial dysfunction in neurons from knockout (gba1
Approximately 40% of preterm births are preceded by microbial invasion the intrauterine space; ascent from vagina being most common pathway. Within cervical canal, antimicrobial peptides and proteins (AMPs) important components barrier which help to prevent ascending vaginal infection. We investigated whether expression AMP, human β-defensin-3 (HBD3), in mucosa pregnant mice could bacterial into uterine cavity. An adeno-associated virus vector containing both HBD3 gene GFP transgene (AAV8...
Significance Chronic inflammatory diseases are characterized by an imbalance between pathogenic T effector cells and regulatory cells. In this report, we demonstrate that decitabine, a cytosine analog, has rapid sustained therapeutic effect in animal models of rheumatoid arthritis. Decitabine selectively targets expressing ENT1, nucleoside transporter, generates robust with the capacity to suppress immune-driven inflammation. This study identifies path toward resetting tolerance autoimmune...
Abstract Argininosuccinate lyase (ASL) is a key enzyme integral to the hepatic urea cycle which required for ammonia detoxification, and citrulline-nitric oxide (NO) NO production. ASL deficient patients present with argininosuccinic aciduria (ASA), an inherited metabolic disease hyperammonaemia chronic systemic phenotype neurocognitive impairment liver disease. deficiency as model of deficiency, shows enhanced nitrosative oxidative stress. Here, we describe dysregulation glutathione...