Julie Méthot

Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial.

We describe the 2-year follow-up of an open-label trial (CT-AMT-011–01) of AAV1-LPLS447X gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPLS447X gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ⩾40% reduction in fasting median plasma triglyceride (TG) at 3–12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 1011 gc kg−1, and cohort 3 (n=8) received 1 × 1012 gc kg−1. Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ⩾40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPLS447X expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.

Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity

The prototype “classic” over‐the‐counter antihistamine diphenhydramine was shown to interact with the polymorphic P450 enzyme CYP2D6. This project was undertaken to investigate (1) whether diphenhydramine inhibits the biotransformation of the clinically relevant CYP2D6 substrate metoprolol in vitro and (2) whether this in vitro interaction results in a clinically significant pharmacokinetic and pharmacodynamic drug interaction in vivo. In vitro incubations were carried out with microsomes obtained from lymphoblastic cells transfected with CYP2D6 complementary deoxyribonucleic acid to determine the type and extent of inhibition. We then randomized 16 subjects with genetically determined high (extensive metabolizers) or low (poor metabolizers) CYP2D6 activity to receive metoprolol (100 mg) in the presence of steady‐state concentrations of diphenhydramine or placebo. In vitro, diphenhydramine was a potent competitive inhibitor of metoprolol α‐hydroxylation, exhibiting an inhibitory constant of 2 μmol/L and increasing the Michaelis‐Menten constant of metoprolol sixfold. In vivo, diphenhydramine decreased metoprolol oral and nonrenal clearances twofold and metoprolol→α‐hydroxymetoprolol partial metabolic clearance 2.5‐fold in extensive metabolizers (all P < .05) but not in poor metabolizers (P > .2). Although the hemodynamic response to metoprolol was unaltered by diphenhydramine in poor metabolizers (P > .05), metoprolol‐related effects on heart rate, systolic blood pressure, and Doppler‐derived aortic blood flow peak velocity were more pronounced and lasted significantly longer in extensive metabolizers receiving diphenhydramine compared with poor metabolizers and extensive metabolizers receiving placebo. We conclude that diphenhydramine inhibits the metabolism of metoprolol in extensive metabolizers, thereby prolonging the negative chronotropic and inotropic effects of the drug. Clinically relevant drug interactions may occur between diphenhydramine and many CYP2D6 substrates, particularly those with a narrow therapeutic index.

Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency

Alipogene tiparvovec (AAV1-LPL(S447X)) gene therapy is developed to prevent complications and decrease the clinical morbidity of lipoprotein lipase deficiency (LPLD). LPLD is an autosomal recessive disease associated with severe hypertriglyceridemia (hyperTG), severe chylomicronaemia, and low HDL. Acute pancreatitis, the most frequent serious clinical LPLD complication, is a complex and heterogeneous inflammatory condition having many causes including hyperTG and chylomicronaemia. In many patients, low fat diet and currently available lipid lowering drugs are ineffective to prevent hyperTG or pancreatitis in LPLD. The clinical development program of alipogene tiparvovec includes observational studies as well as phase I/II and II/III clinical trials. Pooled data are collected on safety and efficacy issues, including the incidence of pancreatitis.

Gene therapy for lipoprotein lipase deficiency.

Purpose of review The present review summarizes the clinical development of adeno-associated viral vector (AAV)1-lipoprotein lipase (LPL)S447X gene therapy (alipogene tiparvovec) for lipoprotein lipase deficiency. Lipoprotein lipase deficiency is a rare inherited disease characterized by severe hypertriglyceridaemia, chylomicronaemia and risk of recurrent pancreatitis or other complications. AAV1-LPLS447X gene therapy is based on the rationale that by adding episomal copies of functional LPL genes into muscle cells lacking active LPL, metabolic function could be improved or restored. Recent findings AAV1-LPLS447X is a nonreplicating and nonintegrating AAV of serotype 1 designed to deliver and express the human LPL gene variant S447X. The clinical development programme for AAV1-LPLS447X consisted of two observational studies, three open-label interventional studies and one case note review analysis. Intramuscular administration of AAV1-LPLS447X was generally well tolerated and was associated with reduction in overall pancreatitis incidence and signs of clinical improvement up to 2 years after administration. Results of interventional studies suggest that markers of postprandial metabolism could be more accurate than fasting plasma triglyceride concentration to monitor the effect of AAV1-LPLS447X. Summary The overall benefit–risk ratio of AAV1-LPLS447X gene therapy appears positive to date, particularly for the patients presenting the highest risk of complications.

Immune Responses to Intramuscular Administration of Alipogene Tiparvovec (AAV1-LPLS447X) in a Phase II Clinical Trial of Lipoprotein Lipase Deficiency Gene Therapy

Cellular immune responses to adeno-associated viral (AAV) vectors used for gene therapy have been linked to attenuated transgene expression and loss of efficacy. The impact of such cellular immune responses on the clinical efficacy of alipogene tiparvovec (Glybera; AAV1-LPL(S447X); uniQure), a gene therapy consisting of intramuscular administration of a recombinant AAV1 mediating muscle-directed expression of lipoprotein lipase (LPL), was investigated. Five subjects with LPL deficiency (LPLD) were administered intramuscularly with a dose of 1 × 10(12) gc/kg alipogene tiparvovec. All subjects were treated with immune suppression starting shortly before administration of alipogene tiparvovec and maintained until 12 weeks after administration. Systemic antibody and T cell responses against AAV1 and LPL(S447X), as well as local cellular immune responses in the injected muscle, were investigated in five LPLD subjects. Long-term transgene expression was demonstrated despite a transient systemic cellular response and a stable humoral immune response against the AAV1 capsid protein. Cellular infiltrates were found in four of the five subjects but were not associated with adverse clinical events or elevation of inflammation markers. Consistent herewith, CD8+ T cells in the infiltrates lacked cytotoxic potential. Furthermore, FoxP3+/CD4+ T cells were found in the infiltrates, suggesting that multiple mechanisms contribute to local tolerance. Systemic and local immune responses induced by intramuscular injection of alipogene tiparvovec did not appear to have an impact on safety and did not prevent LPL transgene expression. These findings support the use of alipogene tiparvovec in individuals with LPLD and indicate that muscle-directed AAV-based gene therapy remains a promising approach for the treatment of human diseases.

Influence of the menstrual cycle on the timing of acute coronary events in premenopausal women

During their reproductive years, women have a low incidence of coronary artery disease (1,2), which increases markedly 10 to 15 years after menopause (3). It has long been hypothesized that this increased risk is at least in part due to the absence of female hormones, in particular, 17 -estradiol (4). This hypothesis was supported by data from epidemiological studies, which suggested that hormone replacement therapy would protect postmenopausal women from coronary artery disease (5– 8). However, recent placebo-controlled trials designed to test the cardioprotective effects of a regimen of estrogens plus progestin have found no reduction in cardiovascular events or progression of angiographic lesions (9 –12). Nevertheless, acute administration of 17 -estradiol affects the vasculature by modulating the nitric oxide–Larginine pathway (13,14), and improves endothelial function (15) and prolongs the time to ST-segment depression and exercise time, in postmenopausal women with coronary artery disease (16). These data suggest that the acute effects of 17 -estradiol could subside rapidly when levels are low during menses. Therefore, we sought to determine whether premenopausal women would be at greater risk of developing an acute coronary event when blood levels of 17 -estradiol levels are low during the menstrual cycle.

Etiology and risk of lactescent plasma and severe hypertriglyceridemia

BACKGROUND Plasma lactescence is a clinical sign of severe hypertriglyceridemia (hyperTG; TG >10 mmol/L), which is likely to be observed more frequently in the next decades because of the growing prevalence of obesity and diabetes worldwide. OBJECTIVE The objective of this study was to describe the clinical expression of plasma lactescence. METHODS A total of 354 subjects with lactescent plasma hyperTG (mean TG ± SD: 17.1 ± 1.8 mmol/L) were classified according to blood appearance, etiology, and biochemical characteristics. The resulting phenotypes were compared with those of 364 normolipidemic controls (TG ≤2 mmol/L) and 487 clear plasma hyperTG subjects (5 < TG ≤9 mmol/L). The association of lactescent plasma with clinical covariates (obesity, coronary artery disease, peripheral artery disease, hypertension, diabetes, glucose intolerance, pancreatitis, and response to TG-lowering drugs) was performed by the use of multiple regression models. RESULTS The risk of pancreatitis increased as a function of the plasma creamy white collar and was the greatest among nonobese individuals with early-onset lactescence not responding to current TG-lowering drugs (familial hyperchylomicronemia). Patients with lactescent plasma and yellowish palmar xanthomas (dysbetalipoproteinemia) responded significantly better to fibrates than the other severe hyperTG phenotypes but were at greater risk of peripheral atherosclerosis. Overweight and obese patients with a creamy supernatant and a cloudy, cream of tomato, infranatant caused by hyper apolipoprotein B showed the most deleterious cardiometabolic risk profile, followed by the severe hyperTG-normal apolipoprotein B phenotype, the most frequent cause of lactescent plasma. CONCLUSION Lactescent plasma hyperTG represents a clinically heterogeneous group of high-risk patients.

Comparison of the efficacy of fibrates on hypertriglyceridemic phenotypes with different genetic and clinical characteristics

&NA; Hypertriglyceridemia is a frequent and heterogeneous clinical trait, which modulates the risk of disease. Fibrates constitute an effective class of triglyceride-lowering agents. Objective To evaluate the effect of fibrates on fasting plasma triglycerides and other lipids levels in hypertriglyceridemia phenotypes with different genetic and clinical characteristics. Methods This study included 146 fasting adults: 15 with lactescent plasma and severe hypertriglyceridemia (triglyceride≥10 mmol/l) and 131 with clear plasma and moderate hypertriglyceridemia (2⩽triglycerides <10 mmol/l). Expost comparisons of the effect of fibrates on fasting triglycerides and other lipids were made using Students paired two-tailed t-test. Results Response to these fibrates differed significantly across the studied hypertriglyceridemia subtypes: patients with severe hypertriglyceridemia because of lipoprotein lipase deficiency and those with moderate hypertriglyceridemia because of glycerol kinase deficiency did not respond at all, whereas patients with palmar xanthomas and severe or moderate hypertriglyceridemia because of apolipoprotein (apo) E resistance (type-III dysbetalipoproteinemia, most often associated with the apo E2 allele) responded significantly better (P<0.001) than all other subtypes on several lipid fractions. Conclusion These results indicate that genetic factors known to contribute to the etiology and clinical expression of hypertriglyceridemia subtypes also modulate the response to triglyceride-lowering drugs.

Salivary pH as a marker of plasma adiponectin concentrations in Women

BackgroundPlasma adiponectin is a significant correlate of the pro-inflammatory cardiometabolic risk profile associated with obesity and type 2 diabetes. Salivary pH is influenced by several cardiometabolic risk components such as inflammation, oxidation and numerous oral and systemic health modulators, including the menopausal status. This study aimed to assess the association between plasma adiponectin concentrations and salivary pH in women according to the menopausal status.MethodUnstimulated saliva collection was performed in 151 Caucasian women of French-Canadian origin (53 premenopausal women (PMW) and 98 menopausal women (MW)). Students t test, ANOVA and linear regression models were used to assess the association between plasma adiponectin concentrations and salivary pH.ResultsPlasma adiponectin levels increased as a function of salivary pH in the whole sample and among MW (r = 0.29 and r = 0.36, p < 0.001). The proportion of the variance of plasma adiponectin levels explained by the salivary pH (R2) was 10.8% (p < 0.001). Plasma adiponectin levels progressively increased across salivary pH quartiles (p = 0.005).ConclusionsThese results suggest that salivary pH is a significant correlate of plasma adiponectin levels in women. With the increasing prevalence of type 2 diabetes and obesity, new technologies should be developed to more easily monitor health status, disease onset and progression. Salivary pH, a simple, inexpensive and non-invasive measure, could be a very promising avenue.

The ACE-DD genotype is associated with endothelial dysfunction in postmenopausal women.

Objective: To evaluate the effects of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the angiotensinogen M235T and the angiotensin II type 1 receptor A1166C polymorphisms, and hormone therapy used on endothelial function in postmenopausal women without manifestation of coronary artery disease. Design: Sixty-four postmenopausal women (42 hormone therapy users and 22 hormone therapy nonusers) without clinical manifestation of coronary artery disease were evaluated using external vascular ultrasonography to measure endothelium-dependent (hyperemic response, flow-mediated dilatation) and -independent (nitroglycerin) dilatation. Genotypes were determined by polymerase chain reaction amplification. Results: Women with the ACE-DD genotype displayed a lower flow-mediated dilatation compared to those with the ACE-II genotype (8.4% ± 3.9% vs 12.6% ± 5.4%, P = 0.04). Endothelial function was not associated with the angiotensinogen M235T and anglotensin II type 1 receptor A1166C polymorphisms. ACE polymorphism seems to modulate endothelial function among postmenopausal women without hormone therapy (8.2% ± 5.1% vs 18.4% ± 5.9% for the DD and the II genotype, respectively, P = 0.02). However, in hormone therapy users, flow-mediated dilatation was similar according to the ACE genotypes. Conclusions: Our findings suggest that ACE-I/D polymorphism is related to endothelial dysfunction in postmenopausal women. Furthermore, a potential interaction between estrogen users and ACE polymorphism on endothelial function may be present.