1.
Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1.
Landmesser, U, Haghikia, A, Leiter, LA, Wright, RS, Kallend, D, Wijngaard, P, Stoekenbroek, R, Kastelein, JJ, Ray, KK
Cardiovascular research. 2021;(1):284-291
Abstract
AIMS: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. METHODS AND RESULTS The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: -0.5%; 500 mg: -1.8%; DD: 100 mg: 1.3%; 200 mg: -0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. CONCLUSION In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.
2.
[Biomarkers of vitamin status in obese school children].
Beketova, NA, Pavlovskaya, EV, Kodentsova, VM, Vrzhesinskaya, OA, Kosheleva, OA, Sokolnikov, AA, Strokova, TV
Voprosy pitaniia. 2019;(4):66-74
Abstract
Inadequate intake of vitamins, noted in children with obesity, reduces the immune system activity, contributes to the metabolic disorders aggravation and may result in comorbidity. The aim of the work was to study sufficiency with vitamins and carotenoids of children with obesity. Material and methods. Examination of vitamin D, B2, C, A, E and β-carotene status in 50 children (male 36.0%) aged 11-17 years [median (Me) - 14 years] with obesity [Z-score body mass index (BMI) >=2.0, Ме=2.86] by determining serum biomarkers has been conducted. Results and discussion. All of the children had an adequate supply with vitamin C (ascorbic acid level >0.4 mg/dL). Low vitamin A status (retinol <30 μg/dl) was revealed in 8% children. Deficiency of vitamin D [25(OH)D<20 ng/ml], vitamin B2 (riboflavin <5 ng/ml) and β-carotene (<10 μg/dl) was detected in 62.0, 38.8 and 74.0% of obese children. The percentage of persons with reduced vitamin E serum level (<0.8 mg/dl) was amounted 54.0%. A severe vitamin D deficit (<10 ng/ml) has been detected in 24.0% of children with Z-score BMI >=2.86 (median value) and has not been observed in children with lower body weight, whose serum β-carotene median was 1.5 fold higher (p<0.05). No one was adequately supplied with all 5 studied vitamins and β-carotene. The combined deficiency of 3 or more vitamins took place in 54.0% of obese children. Synchronously suboptimal serum level of ascorbic acid (<50 μmol/l), β-carotene (<0.4 μmol/l) and α-tocopherol/cholesterol ratio (<5.0 μmol/mmol) which is a cardiovascular disease risk factor, has been found in 28.0% of children. BMI was inversely associated with 25(OH)D serum concentration (ρ=-0.313, р=0.027). There was a pronounced negative correlation between serum level of β-carotene and atherogenic LDL cholesterol (ρ=-0.514, p<0.001). Conclusion. The prevalence of combined vitamin D, tocopherol and carotenoids' inadequacy in obese children indicates the importance of vitamin status correction to reduce the risk of metabolic syndrome.
3.
Differences in GlycA and lipoprotein particle parameters may help distinguish acute kawasaki disease from other febrile illnesses in children.
Connelly, MA, Shimizu, C, Winegar, DA, Shalaurova, I, Pourfarzib, R, Otvos, JD, Kanegaye, JT, Tremoulet, AH, Burns, JC
BMC pediatrics. 2016;(1):151
Abstract
BACKGROUND Glycosylation patterns of serum proteins, such as α1-acid glycoprotein, are modified during an acute phase reaction. The response of acute Kawasaki disease (KD) patients to IVIG treatment has been linked to sialic acid levels on native IgG, suggesting that protein glycosylation patterns vary during the immune response in acute KD. Additionally, the distribution and function of lipoprotein particles are altered during inflammation. Therefore, the aim of this study was to explore the potential for GlycA, a marker of protein glycosylation, and the lipoprotein particle profile to distinguish pediatric patients with acute KD from those with other febrile illnesses. METHODS Nuclear magnetic resonance was used to quantify GlycA and lipoprotein particle classes and subclasses in pediatric subjects with acute KD (n = 75), post-treatment subacute (n = 36) and convalescent (n = 63) KD, as well as febrile controls (n = 48), and age-similar healthy controls (n = 48). RESULTS GlycA was elevated in acute KD subjects compared to febrile controls with bacterial or viral infections, IVIG-treated subacute and convalescent KD subjects, and healthy children (P <0.0001). Acute KD subjects had increased total and small low density lipoprotein particle numbers (LDL-P) (P <0.0001) and decreased total high density lipoprotein particle number (HDL-P) (P <0.0001) compared to febrile controls. Consequently, the ratio of LDL-P to HDL-P was higher in acute KD subjects than all groups tested (P <0.0001). While GlycA, CRP, erythrocyte sedimentation rate, LDL-P and LDL-P/HDL-P ratio were able to distinguish patients with KD from those with other febrile illnesses (AUC = 0.789-0.884), the combinations of GlycA and LDL-P (AUC = 0.909) or GlycA and the LDL-P/HDL-P ratio (AUC = 0.910) were best at discerning KD in patients 6-10 days after illness onset. CONCLUSIONS High levels of GlycA confirm enhanced protein glycosylation as part of the acute phase response in KD patients. When combined with common laboratory tests and clinical characteristics, GlycA and NMR-measured lipoprotein particle parameters may be useful for distinguishing acute KD from bacterial or viral illnesses in pediatric patients.