家族性高コレステロール血症（ホモ接合体）

Familial hypercholesterolemia (FH), most frequently caused by LDLR loss-of-function variants, is a common autosomal dominant disorder that leads to early-onset, life-threatening cardiovascular disease. Therapeutic options for LDLR-deficient homozygous FH (HoFH) are very limited, motivating the development of durable, effective, and LDLR-independent gene therapies. Human genetic studies have linked ASGR1 loss-of-function variants with low serum cholesterol levels and significantly reduced cardiovascular risk, yet in vivo ASGR1 editing has not been explored as a therapeutic strategy for HoFH. Here, using an optimized hepatocyte-specific delivery platform, we achieved 57.6% liver-wide Asgr1 base editing in Ldlr-/- mice, yielding ∼95% reduction of hepatic ASGR1 expression and sustained 40-50% reductions in serum LDL-C, total cholesterol (TC), and triglyceride levels, with a favorable safety profile. Importantly, moderate Asgr1 editing (32.0%) with partial protein suppression (58%) also conferred significant and durable lipid lowering, thereby defining a therapeutically relevant editing window aligned with ASGR1 suppression level in carriers of ASGR1 loss-of-function variants. Benchmarking against Angptl3 editing revealed comparable reductions in LDL-C and TC, while combined Asgr1/Angptl3 editing further enhanced serum cholesterol lowering, suggesting potential benefits of combined editing. Together, these findings establish hepatic ASGR1 base editing as a potent, durable, and LDLR-independent gene therapy strategy for severe HoFH.

INTRODUCTION: The National Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) represents a major source of real-world evidence on lipid metabolism disorders in Spain. This study aims to describe the evolution of the registry, its main scientific contributions, and its current role in the development of precision medicine strategies. METHODS: A descriptive study was conducted based on the analysis of the SEA National Dyslipidemia Registry, complemented by a structured review of the main scientific publications derived from it. Studies related to familial hypercholesterolemia, rare dyslipidemias, response to lipid-lowering therapy, artificial intelligence, and lipoprotein(a) were included. Updated data on the number of patients and participating centers were also incorporated. RESULTS: As of March 2026, the registry includes 10,073 patients from 113 lipid units across Spain. The studies derived from the registry have enabled a detailed characterization of the clinical and genetic profile of familial hypercholesterolemia, identified a significant gap in lipid control in routine clinical practice, and demonstrated substantial variability in response to lipid-lowering therapy. In addition, the role of lipoprotein(a) as an independent cardiovascular risk factor has been further elucidated, including its interaction with other lipid parameters and sex-related differences. The registry has also improved the characterization of rare dyslipidemias, such as familial chylomicronemia syndrome and homozygous familial hypercholesterolemia. The incorporation of artificial intelligence models has enhanced cardiovascular risk stratification. CONCLUSIONS: The SEA National Dyslipidemia Registry has become a reference platform for cardiovascular research in real-world settings, supporting the transition toward precision medicine through the integration of clinical, genetic, and analytical data.

Homozygous familial hypercholesterolemia (HoFH) is a rare and life-threatening genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, leading to accelerated atherosclerotic cardiovascular disease and premature mortality. Conventional lipid-lowering therapies often provide insufficient LDL-C reduction, particularly in patients with minimal or absent LDL receptor (LDLR) function. Evinacumab, an angiopoietin-like protein 3 (ANGPTL3) inhibitor, lowers LDL-C independently of LDLR activity and represents a major therapeutic advance. Here we report two Mexican pediatric patients with HoFH who demonstrated profound LDL-C reductions following initiation of Evinacumab (59% and 68% within the first month of treatment), exceeding reductions observed in pivotal clinical trials. Both patients maintained sustained LDL-C reductions during long-term follow-up (up to 22 months). Importantly, temporary treatment interruption in both cases due to administrative and supply related difficulties limited access to Evinacumab was associated with marked rebound hypercholesterolemia. Reinitiation of therapy led to rapid and substantial lipid reduction, demonstrating a clear dechallenge-rechallenge effect and confirming the relevance of a continuous pharmacologic treatment with ANGPTL3 inhibition. Serial vascular imaging in one patient revealed partial regression of subclavian and carotid artery stenosis, as well as reduced aortic wall thickening following sustained LDL-C reduction; adding evidence to the recently described vascular improvement associated with Evinacumab therapy in pediatric HoFH. Both patients also experienced clinically meaningful improvements in quality of life, and treatment was well tolerated without serious adverse events.