家族性高コレステロール血症（ホモ接合体）

INTRODUCTION: Evinacumab, a monoclonal antibody targeting angiopoietin-like protein 3 (ANGPTL3), has emerged as a promising therapeutic option for severe dyslipidemias. We have conducted a systematic review to evaluate its efficacy across different clinical settings. METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD42026142022). Eligible studies included randomized controlled trials, open-label extension studies, single-arm studies, and observational cohorts involving healthy individuals and patients with hypercholesterolemia or hypertriglyceridemia. Due to the small number of available studies and the absence of the data required for quantitative pooling in other clinical settings, a single-arm meta-analysis was performed exclusively in patients with hypercholesterolemia receiving evinacumab 15 mg/kg every 4 weeks. RESULTS: Overall, 17 studies were included in the systematic review. In hypercholesterolemia, evinacumab consistently reduced LDL-C levels by approximately 50%, with reductions ranging from 42% to 82% across studies. Long-term extension and real-world data confirmed sustained efficacy. Meta-analysis of seven studies including 357 patients receiving evinacumab 15 mg/kg intravenously every 4 weeks demonstrated significant reductions in LDL-C [mean difference (MD) - 48.56%], non-HDL-C (MD - 50.19%), apolipoprotein B (MD - 40.51%), and triglycerides (MD - 53.13%). In hypertriglyceridemia, qualitative evidence showed marked triglyceride lowering, particularly in multifactorial chylomicronemia syndrome, with reductions frequently exceeding 60-80%, whereas responses were limited in familial chylomicronemia syndrome. CONCLUSIONS: Evinacumab provides substantial and sustained lipid-lowering effects, particularly in homozygous familial hypercholesterolemia. Emerging evidence also supports a potential role in severe hypertriglyceridemia, although further studies are needed to define its clinical benefits in this setting.

Despite major advances in lipid-lowering therapies, a significant unmet need remains, particularly for patients with homozygous familial hypercholesterolemia (HoFH), severe heterozygous familial hypercholesterolemia (HeFH), and those who fail to achieve guideline-recommended LDL-C targets. Nucleic acid-based therapeutics have emerged as a transformative approach for treating hypercholesterolemia. Antisense oligonucleotides and small interfering RNAs (siRNAs) have demonstrated durable hepatic gene silencing and have led to approved therapies, while gene replacement and in vivo genome-editing strategies offer the potential for long-lasting, and possibly one-time, interventions. In parallel, microRNAs (miRNAs) have attracted increasing interest because of their ability to coordinately regulate multiple genes involved in lipoprotein metabolism, cholesterol transport, and lipid homeostasis. Human genetic studies further support the importance of miRNA-mediated regulation, exemplified by a rare ~2.5 kb deletion in the distal LDLR 3'UTR ("del2.5") that disrupts miRNA-binding sites and is associated with lifelong low LDL-C levels. This review summarizes recent advances, mechanisms of action, clinical progress, and remaining challenges across antisense oligonucleotides, siRNAs, gene therapy, genome editing, and emerging miRNA-based therapeutics for hypercholesterolemia. As an example of the latter approach, the liver-directed miR-30c analog C2 has demonstrated preclinical activity by coordinately reducing hepatic lipoprotein secretion and lipogenesis while enhancing cholesterol elimination, resulting in reduced LDL-C and atherosclerosis. However, it must be noted that these findings remain preclinical, and further optimization of delivery, pharmacokinetics, safety, and long-term efficacy will be required before clinical evaluation. Continued advances in RNA chemistry, targeted delivery, and genome engineering are expected to further expand the therapeutic landscape for dyslipidemia and cardiovascular disease.

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare genetic disorder caused by biallelic pathogenic variants in LDLRAP1 and may closely mimic homozygous familial hypercholesterolemia. CASE SUMMARY: A 15-year-old boy presented with painless xanthomas over the buttocks and elbows and severe hypercholesterolemia. Total cholesterol was 516 mg/dL, low-density lipoprotein cholesterol (LDL-C) 499 mg/dL, triglycerides 47 mg/dL, and high-density lipoprotein cholesterol 35 mg/dL. Cardiac evaluation was normal, secondary causes were excluded, and first-degree relatives had normal lipid profiles. Whole-exome sequencing identified a novel homozygous LDLRAP1 frameshift variant, c.112dupA (p.Thr38AsnfsTer27), confirming ARH. Computed tomography coronary angiography and computed tomography aortogram showed no atherosclerotic disease, and lipoprotein(a) was 36 mg/dL. DISCUSSION: The patient was treated with atorvastatin, ezetimibe, and bempedoic acid, resulting in a marked reduction in low-density lipoprotein cholesterol to 80 mg/dL at 3-month follow-up. He remained asymptomatic, although no significant xanthoma regression was observed. This case expands the LDLRAP1 mutational spectrum and highlights the importance of genetic testing in severe pediatric hypercholesterolemia with normal family lipid profiles. TAKE-HOME MESSAGE: Early genetic diagnosis helps distinguish ARH from phenotypically similar disorders and guides treatment and counseling.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) causes severe lifelong low-density lipoprotein-cholesterol (LDL-C) elevation and accelerated atherosclerosis from childhood. CASE SUMMARY: A 10-year-old boy presented with extensive tuberous xanthomas and was diagnosed with HoFH due to bi-allelic pathogenic variants in the low-density lipoprotein receptor gene. Baseline LDL-C was 663 mg/dL (17.14 mmol/L). Treatment with atorvastatin, followed by rosuvastatin and ezetimibe, reduced LDL-C to 235 mg/dL (6.08 mmol/L) with marked regression of xanthomas. One year later, he developed exertional chest pain. Coronary angiography and intravascular ultrasound demonstrated early coronary atherosclerosis with a nonobstructive 28% stenosis of the right coronary artery. DISCUSSION: This case provides an opportunity to discuss the role and limitations of currently available lipid-lowering therapies in HoFH. We review current lipid-lowering therapies and the challenges of achieving LDL-C targets in patients with HoFH, particularly in resource-limited settings. TAKE-HOME MESSAGE: Early recognition and aggressive LDL-C lowering are essential in HoFH to prevent atherosclerosis.