Correction of Fanconi Anemia Group C Hematopoietic Stem Cells Following Intrafemoral Gene Transfer

The main cause of morbidity and mortality in Fanconi anemia patients is the development of bone marrow (BM) failure; thus correction of hematopoietic stem cells (HSCs) through gene transfer approaches would benefit FA patients. However, gene therapy trials for FA patients using ex vivo transduction protocols have failed to provide long-term correction. In addition, ex vivo cultures have been found to be hazardous for FA cells. To circumvent negative effects of ex vivo culture in FA stem cells, we tested the corrective ability of direct injection of recombinant lentiviral particles encoding FancC-EGFP into femurs of FancC−/− mice. Using this approach, we show that FancC−/− HSCs were efficiently corrected. Intrafemoral gene transfer of the FancC gene prevented the mitomycin C-induced BM failure. Moreover, we show that intrafemoral gene delivery into aplastic marrow restored the bone marrow cellularity and corrected the remaining HSCs. These results provide evidence that targeting FA-deficient HSCs directly in their environment enables efficient and long-term correction of BM defects in FA

Molecular Spectrum of Autosomal Dominant Hypercholesterolemia in France

Autosomal Dominant Hypercholesterolemia (ADH), characterized by isolated elevation of plasmatic LDL cholesterol and premature cardiovascular complications, is associated with mutations in 3 major genes: LDLR (LDL receptor), APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin-kexin type 9). Through the French ADH Research Network, we collected molecular data from 1358 French probands from eleven different regions in France. Mutations in the LDLR gene were identified in 1003 subjects representing 391 unique events with 46.0% missense, 14.6% frameshift, 13.6% splice, and 11.3% nonsense mutations, 9.7% major rearrangements, 3.8% small in frame deletions/insertions, and 1.0% UTR mutations. Interestingly, 175 are novel mutational events and represent 45% of the unique events we identified, highlighting a specificity of the LDLR mutation spectrum in France. Furthermore, mutations in the APOB gene were identified in 89 probands and in the PCSK9 gene in 10 probands. Comparison of available clinical and biochemical data showed a gradient of severity for ADH-causing mutations: FH=PCSK9>FDB>‘Others’ genes. The respective contribution of each known gene to ADH in this French cohort is: LDLR 73.9%, APOB 6.6%, PCSK9 0.7%. Finally, in 19.0% of the probands, no mutation was found, thus underscoring the existence of ADH mutations located in still unknown genes. © 2010 Wiley-Liss, Inc

SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia

International audienceBackground and aims: Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population.Methods: Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population.Results: We included HeFH (n=1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively).Conclusions: This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients

Early Coronary Calcifications are Related to Cholesterol Burden in Heterozygous Familial Hypercholesterolemia

International audienceBackgroundThe identification of high-risk patients with Heterozygous Familial Hypercholesterolemia (HeFH) that may benefit from early treatment is challenging. Coronary Artery Calcification (CAC) score accounts for coronary atherosclerotic burden. It has proven its accuracy in cardiovascular risk (CVR) assessment in the general population but data in HeFH are lacking.ObjectiveThe aim of our study was to assess CAC prevalence and its relationship with lifelong cholesterol exposure, calculated by Total Cholesterol Burden (TCB) in patients with HeFH.Methods112 HeFH patients (50% males, median age 45) regularly followed-up since diagnosis were prospectively recruited at Pitié-Salpêtrière Hospital, Paris, France. CAC score was assessed using non contrast multi-detector computed tomography. TCB was calculated as total cholesterol (TC) x age at diagnosis plus annually assessed TC.ResultsThe prevalence of CAC was 58%. Patients without CAC showed lower TCB than patients with CAC (298±110 vs 417.9±89 mmol-years/l, p<0.001). Among patients <45 (n=56), 39% exhibited CAC and a higher TCB compared to patients without CAC (352±71 vs 255±88 mmol-years/l, p<0.001) due to higher TC levels at diagnosis (10.2±2 vs 8.7±2 mmol/l, p=0.01). Multivariate analysis indicated that TCB was independently associated toCAC.ConclusionsAsymptomatic HeFH subjects exhibit early coronary atherosclerosis directly associated with TCB. Cholesterol burden and CAC score may be useful to identify higher risk HeFH patients who can benefitfrom earlier and more aggressive treatment

The very high cardiovascular risk in heterozygous familial ă hypercholesterolemia: Analysis of 734 French patients

International audienceBACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a ă genetic disease causing high levels of low-density lipoprotein ă cholesterol (LDL-C). Although this population is at high cardiovascular ă (CV) risk, the risk is variable within patients depending on additional ă risk factors. CV disease risk groups have been defined by the Nouvelle ă Societe Francophone d'Atherosclerose (NSFA) and by the National Lipid ă Association recommendations. ă OBJECTIVES: The study aimed to describe a sample of French heFH ă patients, comparing patients at very high risk (VHR) and patients at ă high risk in terms of demographic and clinical characteristics as well ă as biological measurements and disease management. ă METHODS: Cross-sectional retrospective analysis on 734 patients ă hospitalized after 2005 in 5 academic centers. ă RESULTS: When considering NSFA classification, 550 (74.9%) patients ă belonged to the VHR group. Most patients in the VHR group presented more ă than 1 risk factor, the most prevalent ones being Lp(a) > 50 mg/dL and ă smoking. Patients in the VHR group were older (50.6 vs 45.0 years old, P ă =.0002), and presented a higher body mass index (25.5 kg/m(2) vs 23.3 ă kg/m(2), P <.0001). The proportion of patients with carotid arterial ă plaque was higher in the VHR group (59.8% vs 48.6%, P =.06). Total ă cholesterol (2.41 g/L on average) and LDL-C (1.65 g/L on average) were ă not found to be significantly different. Maximum level of lipid-lowering ă treatments were used in 34% of cases in the VHR group, significantly ă higher than 16% in the high-risk group (P =.001). Very similar results ă were found when using the National Lipid Association recommendations. ă CONCLUSION: This study provides a detailed description of French heFH ă patients according to their CV risk. Patients with very high CV risk had ă usually more advanced carotid plaques and were treated with heavier ă lipid-lowering drugs although their LDL-C level remained similar. This ă highlights the significant burden of this population. (C) 2016 National ă Lipid Association. All rights reserved