A5056737617- Biochemical and Molecular Research
- Cytomegalovirus and herpesvirus research
- Metabolism and Genetic Disorders
- Neonatal Health and Biochemistry
- Pulmonary Hypertension Research and Treatments
- Adenosine and Purinergic Signaling
- Porphyrin Metabolism and Disorders
- Immunodeficiency and Autoimmune Disorders
- HIV/AIDS drug development and treatment
- Gout, Hyperuricemia, Uric Acid
- Congenital Heart Disease Studies
- Glycogen Storage Diseases and Myoclonus
- Acute Lymphoblastic Leukemia research
- Virus-based gene therapy research
- Mitochondrial Function and Pathology
- Pleural and Pulmonary Diseases
- Kidney Stones and Urolithiasis Treatments
- Pneumocystis jirovecii pneumonia detection and treatment
- Genomic variations and chromosomal abnormalities
- Urticaria and Related Conditions
- Cancer, Hypoxia, and Metabolism
- Pancreatitis Pathology and Treatment
- Skin and Cellular Biology Research
- Dermatological and Skeletal Disorders
- Autoimmune Bullous Skin Diseases
Guy's and St Thomas' NHS Foundation Trust
2011-2025
St Thomas' Hospital
2013-2024
Medical University of Sofia
2018
St. Thomas Hospital
1998-2013
University College London
1984-2012
TGS (United Kingdom)
2012
Guy's Hospital
1999-2009
Bath Institute for Rheumatic Diseases
2008
Rutgers, The State University of New Jersey
2005
GTx (United States)
2003
Gene therapy can restore immune and metabolic function in patients with adenosine deaminase immunodeficiency.
Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% 28% patients and majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results benign accumulation inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, ITPase deficient patients, potentially toxic 6-thio-ITP predicted accumulate. The association between polymorphism ITPA gene adverse...
Sensitive high performance liquid chromatography techniques, which differentiate between purine and pyrimidine ribonucleoside deoxyribonucleoside triphosphates, were used to quantify pools in phytohemagglutinin-stimulated T-lymphocytes (98% CD4+ CD8+) from healthy volunteers. The importance of de novo synthesis salvage was evaluated by incubating the cells with 14C-radiolabeled precursors (40 μM), azaserine (20 μM; a glutamine antagonist), ribavirin (50 an IMP dehydrogenase inhibitor). We...
The mode of action Leflunomide, an immunomodulatory drug used in rheumatoid arthritis, is debated. This study, using <sup>14</sup>C-labeled <i>de novo</i> purine and pyrimidine synthesis precursors, proves conclusively that the prime target proliferating human T-lymphocytes biosynthesis at level dihydroorotic-acid dehydrogenase. Leflunomide (25 50 μm), like Brequinar (0.5 1 a demonstrated dehydrogenase inhibitor, was cytostatic, not cytotoxic, with proliferation being halted G<sub>1</sub>...
Gene therapy is a promising treatment option for monogenic diseases, but success has been seen in only handful of studies thus far. We now document successful reconstitution immune function child with the adenosine deaminase (ADA)-deficient form severe combined immunodeficiency (SCID) following hematopoietic stem cell (HSC) gene therapy. An ADA-SCID who showed poor response to PEG-ADA enzyme replacement was enrolled into clinical study. Following cessation therapy, autologous CD34+ HSCs were...
Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions a major clinical problem, often necessitating discontinuation. The aim this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. Toxicity in first four cycles 5-fluorouracil or capecitabine-based chemotherapy were recorded series 430 patients. association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity analysed...
Gene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). However, current gRV have significant potential insertional mutagenesis as reported in clinical trials other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy (GT), we generated a self-inactivating lentiviral vector (LV) with codon-optimized human cADA under control...
Proliferative defects have been reported at the level of DNA synthesis, even in T-lymphocytes from asymptomatic human immunodeficiency virus type-1+ (HIV-1+) patients. Since purine and pyrimidine ribonucleotide availability is crucial for proliferation, we compared ability HIV-1− HIV-1+ (>95% CD4+ CD8+) to activate de novo biosynthetic salvage pathways following phytohemagglutinin stimulation using 14C-labeled precursors.The striking abnormality already detectable patients' cells was...
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease caused by mutations in nuclear TYMP gene, encodes for thymidine phosphorylase, enzyme required normal metabolism of deoxynucleosides, thymidine, deoxyuridine. The subsequent elevated systemic concentrations deoxynucleosides lead to increased intracellular their corresponding triphosphates, ultimately mitochondrial...
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for enzyme phosphorylase. There are currently no approved treatments MNGIE. The aim this study was to investigate safety, tolerability, and efficacy replacement therapy treatment In single centre study, three adult patients with MNGIE received intravenous escalating doses...
Developmental retardation was a prominent clinical feature in six infants from three kindreds deficient the enzyme purine nucleoside phosphorylase (PNP) and present before development of T cell immunodeficiency. Guanosine triphosphate (GTP) depletion noted erythrocytes all surviving homozygotes equivalent magnitude to that found Lesch-Nyhan syndrome (complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency). The similarity between neurological complications both disorders...
Polyethylene glycol‐conjugated adenosine deaminase (pegademase) is used for enzyme replacement therapy patients with severe combined immunodeficiency caused by deficiency. The entrapment of pegademase within human energy‐replete carrier erythrocytes using a hypo‐osmotic dialysis procedure was investigated the objective prolonging in vivo circulatory half‐life and maintaining therapeutic blood levels. Native unmodified (ADA) similarly studied. efficiency low (9%) whereas native ADA...
Inosine triphosphate pyrophosphatase (ITPase) deficiency occurs with polymorphic frequencies in Caucasians and results the benign accumulation of inosine nucleotide ITP. In 62 patients treated azathioprine for inflammatory bowel disease, ITPA 94C>A deficiency-associated allele was significantly associated adverse drug reactions (OR 4.2, 95% CI 1.6-11.5, p = 0.0034). Significant associations were found flu-like symptoms 4.7, 1.2-18.1, 0.0308), rash 10.3, 4.7-62.9, 0.0213) pancreatitis 6.2,...
Abstract Adenosine deaminase (ADA) deficiency is an inherited disorder which leads to elevated cellular levels of deoxyadenosine triphosphate (dATP) and systemic accumulation its precursor, 2‐deoxyadenosine. These metabolites impair lymphocyte function, inactivate S‐adenosylhomocysteine hydrolase (SAHH) respectively, leading severe immunodeficiency. Enzyme replacement therapy with polyethylene glycol‐conjugated ADA available, but efficacy reduced by anti‐ADA neutralising antibody formation....