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Familial hypercholesterolemia (FH) is a genetic disease, usually with onset during childhood, characterized by elevated blood LDL cholesterol levels and potentially associated with severe cardiovascular complications. Concerning mutated genes in FH, such as LDLR , a small subset of FH patients presents a homozygous genotype, resulting in homozygous FH (HoFH) disease with a generally aggressive phenotype. Besides statins, ezetimibe and PCSK9 inhibitors, lomitapide (an anti-ApoB therapy) was also approved in 2012–2013 as an adjunctive treatment for HoFH. Despite its clinical efficacy, lomitapide administration should be done with caution because of the possible occurrence of side effects, such as hepatosteatosis, increased blood transaminase levels and gastrointestinal symptoms, as well as the possible deleterious interactions with other drugs. In this context, we decided to report the main available evidence on the management and monitoring of HoFH patients treated with lomitapide and to accompany this literature review with a description of our clinical experience with a subset of six HoFH patients. In conclusion, this paper aims to address an important topic for HoFH-related clinical practice that, to our knowledge, is not yet formally regulated by proper national and/or international guidelines. [ABSTRACT FROM AUTHOR]

Background: The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat Familial Chylomicronemia Syndrome (FCS). Cases of decreased platelet count are reported among patients treated with volanesorsen. The aim of the study was to evaluate platelet function and thrombin generation (TG) assessment in FCS patients receiving volanesorsen. We performed a cross-sectional study on FCS patients treated with volanesorsen. Methods: Changes in platelet count PLC were assessed from baseline to Tw12 and Tw36. To assess TG, samples were processed by CAT (with PPP-reagent LOW). The results were expressed by the thrombogram graphic (thrombin variation over time); LagTime; endogenous thrombin potential (ETP); peak; time to reach peak (ttpeak), StartTail and Velocity Index. Platelet aggregation was assessed by testing different agonists using the turbidimetry method. Results: Four FCS patients and four matched healthy controls were included in the present study. Changes in PLC were 30% at Tw12 and 34% at Tw36. Thrombin generation results showed values in the normal range (for patients and controls, respectively, LagTime:10.42 ± 4.40 and 9.25 ± 0.99; ttPeak:14.33 ± 4.01 and 13.10 ± 0.67; StartTail: 32.13 ± 3.54 and 29.46 ± 1.69; Velocity Index: 20.21 ± 3.63 and 33.05 ± 13.21; ETP: 599.80 ± 73.47 and 900.2 ± 210.99; peak value: 76.84 ± 1.07 and 123.30 ± 39.45) and no significant difference between cases and controls. Platelet aggregation test showed values in range, with no significant difference compared to healthy controls. Conclusions: Our study showed for the first time that no significant changes in general hemostasis assessed by TG and in platelet function were observed in FCS patients receiving volanesorsen. [ABSTRACT FROM AUTHOR]

Despite major advances in prophylaxis, no repeated dosing regimen with currently employed extended-half-life or non-factor products replaces the advantages of a long-term cure in persons with severe congenital hemophilia A and B (HA, HB). They indeed live with the risk of breakthrough bleedings, and treatment is still invasive, both physically and psychologically. Early studies showed that adeno-associated virus-based in vivo gene therapy (AAV-based in vivo GT), could convert haemophilia persons from a severe to mild a phenotype for years. However, the proportion of the hemophilia population likely to benefit from this transformative strategy was uncertain. Current evidence is expanding the eligibility criteria, and helps to predict risks, complications and unexpected side effects of this advanced treatment. Thus, among future options, AAV-based in vivo GT is likely to become the treatment of choice in HA and HB, if real-life data confirm its negligible short-term adverse events. However, while the global use of AAV-based in vivo GT is endorsed as a key objective of future studies in hemophilia, the liberating capability of a potentially one-off treatment on individuals with chronic diseases for whom lifelong cure has been inaccessible so far remains to be thoroughly recognized by government bodies. This is critical for reimbursement agencies to absorb the cost of the cure and calls for a partnership between health care systems and the pharmaceutical industry. However, bridging the gap between the costs of the advanced treatments approved for commercialization and their readiness to persons with HA and HB is still a challenging task. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) comprises high LDL-cholesterol (LDL-c) levels and high cardiovascular disease risk. In the absence of pathogenic variants in causative genes, a polygenic basis was hypothesized. Methods: In a population of 418 patients (excluding homozygotes) with clinical suspicion of FH, the FH-causative genes and the regions of single nucleotide polymorphisms (SNPs) included in 12-SNP and 6-SNP scores were sequenced by next-generation sequencing, allowing for the detection of pathogenic variants (V+) in 220 patients. To make a comparison, only patients without uncertain significance variants (V−/USV−) were considered (n = 162). Results: Higher values of both scores were observed in V+ than in V−. Considering a cut-off leading to 80% of V−/USV− as score-positive, a lower prevalence of patients positive for both 12-SNP and 6-SNP scores was observed in V+ (p = 0.010 and 0.033, respectively). Mainly for the 12-SNP score, among V+ patients, higher LDL-c levels were observed in score-positive (223 mg/dL -IQR 187-279) than in negative patients (212 mg/dL -IQR 162–240; p = 0.006). Multivariate analysis confirmed the association of scores and LDL-c levels independently of age, sex, and presence of pathogenic variants and revealed a greater association in children. Conclusions: The 12-SNP and 6-SNP polygenic scores could explain hypercholesterolemia in patients without pathogenic variants as well as the variability of LDL-c levels among patients with FH-causative variants. [ABSTRACT FROM AUTHOR]