Efficacy, pharmacokinetics, and safety in the mouse and primate retina of dual AAV vectors for Usher syndrome type 1B.

Gene therapy of Usher syndrome type 1B (USH1B) due to mutations in the large () gene is limited by the packaging capacity of adeno-associated viral (AAV) vectors. To overcome this, we have previously developed dual AAV8 vectors which encode human (dual AAV8.).

Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI.

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities.

Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI.

In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.

"RCL-Pooling Assay": A Simplified Method for the Detection of Replication-Competent Lentiviruses in Vector Batches Using Sequential Pooling.

Nonreplicative recombinant HIV-1-derived lentiviral vectors (LV) are increasingly used in gene therapy of various genetic diseases, infectious diseases, and cancer. Before they are used in humans, preparations of LV must undergo extensive quality control testing. In particular, testing of LV must demonstrate the absence of replication-competent lentiviruses (RCL) with suitable methods, on representative fractions of vector batches.

Identification of cis- and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels.

Rationale: Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings.

Objective: Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis.

Association study of gene polymorphisms involved in vascular alterations in elderly hypertensives with subjective memory complaints.

Background: We have recently shown that vascular abnormalities are associated with cognitive impairment as well as with white matter hyperintensities (WMH) in elderly hypertensive patients presenting with subjective memory complaints (SMC), a population at high risk of developing dementia. The aim of the present study was to identify genetic variants associated with the degree of cognitive impairment and the severity of WMH in the same study population, focusing on genes involved in vascular alterations.

Methods: 50 gene polymorphisms known to be associated with vascular alterations (blood pressure regulation, lipid and homocysteine metabolism, thrombosis and inflammation) were genotyped using a multilocus genotyping assay in 369 elderly treated hypertensive patients >60 years of age and presenting with SMC but no dementia.

Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males.

Background: The sensitivity of chronic lymphocytic leukemia (CLL) cells to current treatments, both in vitro and in vivo, relies on their ability to activate apoptotic death. CLL cells resistant to DNA damage-induced apoptosis display deregulation of a specific set of genes.

Methods: Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent in situ labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real-time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied.

Metabolic syndrome-related composite factors over 5 years in the STANISLAS family study: genetic heritability and common environmental influences.

Background: We estimated genetic heritability and common environmental influences for various traits related to metabolic syndrome in young families from France.

Methods: At entrance and after 5 years, nineteen traits related to metabolic syndrome were measured in a sample of families drawn from the STANISLAS study. In addition, 5 aggregates of these traits were identified using factor analysis.

Drug metabolizing enzymes and transporters mRNA in peripheral blood mononuclear cells of healthy subjects: biological variations and importance of pre-analytical steps.

Quantification in peripheral blood mononuclear cells of mRNA of drug metabolizing enzymes or drug targets could give interesting, new information in the field of pharmacogenomics and molecular mechanisms. However, for the interpretation of these data, it is necessary to know mRNA biological variations. In this review, we propose a strategy based on the production and interpretation of clinical chemistry reference values.

Parental precocious influences on offspring cardiovascular risk markers: an exploratory study in the STANISLAS Cohort.

Familial history of cardiovascular disease is acknowledged as a risk indicator in offspring. The aim of this study was to assess whether the cardiovascular risk factors in parents predicted the risk of their children developing cardiovascular disease in a French population: the STANISLAS Cohort, in which Caucasian biparental families with at least two siblings were followed for 5 years. Silent risk factors (blood pressure, lipid traits, glycemia, BMI and waist circumference) of children were compared according to their parents' risk status in a subsample of 693 families.

Candidate gene microarray analysis in peripheral blood cells for studying hypertension/obesity.

Aims: The gene expression of 182 cardiovascular candidate genes was measured in high quality groups of individuals (n = 20) by microarrays to determine whether a subset of genes would discriminate obese and hypertensive individuals, in spite of the existence of a close link between these two cardiovascular risk factors.

Materials & Methods: The results were validated on the 20 subjects used for microarray analysis and on 62 additional individuals by real-time PCR.

Results: The first analysis, where patient groups were compared with healthy subjects, revealed 15 out of 182 genes that differed in hypertensive, obese or obesity-related hypertensive individuals.

Pharmacogenomics and antihypertensive drugs: a path toward personalized medicine.

Pharmacogenomics focuses on genes and the transcriptome and proteome. It has the potential to enhance healthcare management by improving disease diagnosis and implementing treatments adapted to each patient. Previously, pharmacogenetics of candidate genes focused on clinical research.

Transcription factor and drug-metabolizing enzyme gene expression in lymphocytes from healthy human subjects.

We aimed to measure simultaneously the expression of drug-metabolizing enzymes (DME) and transcription factors (TF) with high importance in cardiovascular physiopathology in lymphocytes from healthy subjects. RNA was isolated from peripheral blood mononuclear cells (PBMC) of 20 subjects from the Stanislas Cohort. We used a microarray approach to measure 16 DME and 13 TF.

Natural phosphorylation of CD5 in chronic lymphocytic leukemia B cells and analysis of CD5-regulated genes in a B cell line suggest a role for CD5 in malignant phenotype.

Chronic lymphocytic leukemia (CLL) results in the accumulation of B cells, presumably reflecting the selection of malignant cell precursors with Ag combined with complex alterations in protein activity. Repeated BCR stimulation of normal B cells leads to anergy and CD5 expression, both of which are features of CLL. Because CD5 is phosphorylated on tyrosine following BCR engagement and negatively regulates BCR signaling in normal B cells, we investigated its phosphorylation status and found it to be naturally phosphorylated on tyrosine but not on serine residues in CLL samples.

Peripheral blood mononuclear cells (PBMCs): a possible model for studying cardiovascular biology systems.

Background: The inflammation system, alone or in relation to or interaction with other cardiovascular pathways, is suggested to be the central pathway in the development and progression of cardiovascular diseases. The aim of the present investigation was to propose a specific and informative model for exploring this hypothesis.

Methods: In a biological system approach, we studied the expression of 182 candidate cardiovascular genes in peripheral blood mononuclear cells (PBMCs), cells that provide specific information on the inflammatory pathway.

Interaction between CYP1A1 T3801C and AHR G1661A polymorphisms according to smoking status on blood pressure in the Stanislas cohort.

Background: CYP1A1, one of the key enzymes in detoxifying toxic components produced during cigarette smoking, is regulated by aromatic hydrocarbon receptor (AHR). A CYP1A1 T3801C polymorphism, associated with a higher CYP1A1 inducibility and enhanced catalytic activity, has been linked to stroke, triple vessel disease and may, therefore, be associated with blood pressure (BP). The relation of the widely studied G1661A polymorphism of the human AHR gene with BP is unknown.

Genetic variants predisposing to cardiovascular disease.

Purpose Of Review: The goal of this review is to provide an update on the most recent and relevant findings in the area of genotype-phenotype associations as well as the relationships between genetic factors and cardiovascular disease risk markers and events. In addition, emphasis will be placed on the methodological problems associated with studying the genetics of complex disorders, specifically cardiovascular diseases.

Recent Findings: Genes associated with cardiovascular disease predisposition have been examined, including traditional cardiovascular disease candidate genes, such as ACE, AGT, eNOS, PON and MTHFR, new loci that have recently been added to the growing list of cardiovascular disease candidate genes (i.

Pharmacogenomics and cardiovascular drugs: need for integrated biological system with phenotypes and proteomic markers.

Personalized medicine is based on a better knowledge of biological variability, considering the important part due to genetics. When trying to identify involved genes and their products in differential cardiovascular drug responses, a five-step strategy is to be followed: 1) Pharmacokinetic-related genes and phenotypes (2) Pharmacodynamic targets, genes and products (3) Cardiovascular diseases and risks depending on specific or large metabolic cycles (4) Physiological variations of previously identified genes and proteins (5) Environment influences on them. After summarizing the most well-known genes involved in drug metabolism, we will take as example of drugs, the statins, considered as very important drugs from a Public-Health standpoint, but also for economical reasons.

Genetic determinants of blood pressure regulation.

Hypertension is a multifactorial disorder that probably results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. Existing evidence suggests that the genetic contribution to blood pressure variation is about 30-50%. Although a number of candidate genes have been studied in different ethnic populations, results from genetic analysis are still inconsistent and specific causes of hypertension remain unclear.

The Leu554Phe polymorphism in the E-selectin gene is associated with blood pressure in overweight people.

Background: Associations between circulating concentrations of E-selectin, blood pressure and obesity, and between the Leu554Phe (L/F554) polymorphism and blood pressure have been documented.

Objectives: To investigate how the E-selectin L/F554 polymorphism is involved in longitudinal blood pressure changes, and how this polymorphism interacts with body mass index (BMI) on blood pressure.

Design And Participants: For this study, 478 men and 546 women were selected from the Stanislas cohort, a French longitudinal study of volunteers for a free health check-up.