RARE DISEASE
Homozygous familial hypercholesterolemia
Homozygous familial hypercholesterolemia
Homozygous familial hypercholesterolemia
Synonyms: HoFH
Synonyms: HoFH
Synonyms: HoFH
Drug discovery
18
drugs
With orphan designations
Overview
Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal dominant or recessive disorder caused by biallelic mutations in LDLR, APOB, PCSK9, or LDLRAP1. It results in lifelong extreme LDL-C elevation (>400 mg/dL untreated), accelerated atherosclerosis, and premature cardiovascular events (often before age 20 without treatment). Diagnosis requires genetic testing and early multimodal therapy to mitigate cardiovascular risk.
Therapies
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
1,400 drug discovery papers about Homozygous familial hypercholesterolemia, with 2 first-in-class and 25 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,400 drug discovery papers about Homozygous familial hypercholesterolemia, with 2 first-in-class and 25 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-06-26 | Women with Homozygous Familial Hypercholesterolemia and Impact on Reproductive Life from Menarche to Menopause: Long-Term Case Series Observational Study
Homozygous familial hypercholesterolemia (HoFH) is a genetic disease in which LDL-C is high at birth, causing cardiovascular disease. Reproductive issues in women are also caused by lipid-lowering therapies (LLTs) that must be interrupted during pregnancy and breastfeeding. The only safe choice during pregnancy is lipoprotein apheresis (LA), although there are limited data regarding fertility, pregnancy, and menopause. This long-term case series observational study examined 23 genetically confirmed HoFH women in a tertiary health facility, obtaining clinical, cardiovascular, biochemical, and reproductive information through medical records and structured interviews. Cardiovascular disease and aortic valve disease were found in 48% and 52%, respectively; four women died prematurely. Menarche (12.1 years) and menopause (52.0 years) were in the normal range. The majority of these had regular menstrual cycles; there was one case of polycystic ovary syndrome. Twelve women became spontaneously pregnant. Obstetric complications included preterm delivery, gestational diabetes, hypertension, and fetal growth restriction. This study showed that continuous LA during pregnancy was associated with better lipid control and maternal-fetal outcomes, but cardiovascular impairment was observed in the case of interruption of LLT. LLT interruption affects the inherited lipid disorder, and a very short period of breastfeeding is recommended. HoFH in women under treatment has no impact on the menstrual cycle or on the timing of menopause. Pregnancy is a high-risk condition that needs the care of a multidisciplinary team. The need to ensure continuous LA, systematic reproductive counseling, early cardiovascular examination, and aligned lifelong care is critical in maximizing the outcome of HoFH women.
2026-06-24 | Synergistic "targeting and blockade" strategy via engineered exosomes and clinical ultrasound contrast agent for hepatocyte-targeted mRNA delivery.
Homozygous familial hypercholesterolemia (HoFH) presents a persistent and difficult-to-treat condition. This recalcitrance stems largely from loss-of-function mutations within the low-density lipoprotein receptor (LDLR) gene, which severely undermine the efficacy of standard therapeutic regimens. Here, we report a bioinspired "targeting and blockade" strategy for the efficient delivery of functional Ldlr mRNA to hepatocytes. This approach is realized through a rationally designed platform, Szd + AP@ExoE-Ldlr, which integrates APOA1-functionalized exosomes for hepatocyte-targeted delivery with a preemptive macrophage blockade using the clinical ultrasound contrast agent Sonazoid (Szd). The APOA1 modification confers specific recognition by the scavenger receptor class B type 1 on hepatocytes, while the pre-saturation of Kupffer cells with Szd significantly mitigates nonspecific clearance by the mononuclear phagocyte system (MPS). In a HoFH murine model, this synergistic strategy markedly enhanced the accumulation of exosomes in hepatocytes and achieved robust restoration of hepatic LDLR expression. Consequently, it elicited a profound correction of the atherogenic lipid profile and substantially attenuated the progression of atherosclerosis. A comprehensive biosafety evaluation confirmed the excellent biocompatibility of this platform. Our work provides a promising and broadly applicable solution for the treatment of liver-related genetic disorders by simultaneously overcoming the critical barriers of targeted delivery and MPS evasion.
2026-04-17 | Liver transplantation in severe homozygous familial hypercholesterolaemia: a scoping review.
Liver transplantation is the only known potentially curative treatment for homozygous familial hypercholesterolaemia (HoFH). While this procedure often normalises low-density lipoprotein cholesterol (LDL-C) levels and can reverse coronary atherosclerosis and regress xanthomata, its long-term risks and benefits remain elusive. The purpose of this review was to examine the extant literature on the safety and efficacy of liver transplantation in patients with HoFH. A scoping review was conducted for relevant literature primarily focused on safety (e.g. surgical complications, rejection, immunosuppressive therapy, mortality) and effectiveness outcomes (e.g. serum LDL-C levels, xanthoma changes, atherosclerotic cardiovascular disease or events) of liver transplantation in severe HoFH. The PRISMA-ScR guideline was followed. We searched five databases (Medline, Embase, Global Health, Web of Science and CINAHL) from inception to September 2025. A total of 76 studies and 212 cases were included. The majority (53%) of studies were case reports. Liver transplantation was done mostly in children, genetically or phenotypically diagnosed with HoFH. The median follow-up time for individuals was 3.5 years. While the effectiveness of liver transplantation with reference to LDL-C reduction and xanthomata regression were well documented, long-term outcomes such as cardiovascular events and mortality were not consistently reported. While liver transplantation holds great potential for normalising circulatory LDL-C levels in patients with HoFH, due to the rare nature of HoFH, the current literature remains incomplete concerning its safety and efficacy. To fill this gap, future efforts should utilise liver transplantation registries, to increase sample size and standardise longer-term follow-up.
2026-01-21 | Clinical and Subclinical Atherosclerotic Disease in Adolescents With Familial Hypercholesterolemia.
Familial hypercholesterolemia is primarily a disorder of reduced low-density lipoprotein (LDL) clearance, which can be inherited in either homozygous or heterozygous form. Despite the availability of various modalities to achieve target LDL cholesterol levels, inadequate control remains a significant risk factor for accelerated atherosclerosis in the pediatric population. Moreover, the occurrence of coronary artery disease in adolescents poses unique management challenges given the limited representation of this age group in clinical trials. We report 2 cases of coronary artery disease and 1 case of subclinical atherosclerosis in adolescent patients with genetically confirmed familial hypercholesterolemia, outlining the diagnostic work-up, challenges in achieving LDL cholesterol control, measures undertaken, including plasma exchange, and revascularization strategies using drug-eluting stents or drug-coated balloons, in accordance with current guidelines.
2025-12-01 | Homozygous familial hypercholesterolemia in a child: A clinical effect of regular lipoprotein apheresis in a multispecialty children’s hospital
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited condition associated with extremely elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), leading to early vascular atherosclerosis. Here we report a clinical observation of a girl with early-onset multiple xanthomatosis (the age of clinical symptom onset was 1.5 years) and a genetically confirmed homozygous variant, c.1729T>C, in the LDLR gene (p.W577R). The diagnosis was established at the age of 3 (TC up to 25 mmol/L; TC level time profile remained at 23.5 mmol/L, LDL-C 22.1 mmol/L). However, a targeted lipidlowering diet was not arranged in a consistent manner, and the drug therapy was not conducted, which reflected physicians' poor awareness and lack of routing of patients. The patient has been followed at the Z. A. Bashlyaeva Children's City Clinical Hospital of the Moscow Health Department (Competence Center for Screening and Treatment of Lipid Disorders in Children and Adolescents) since the age of 6.5 years. All attempts to choose any beneficial combination lipid-lowering pharmacotherapy (rosuvastatin, ezetimibe, evolocumab) have not yielded a clinically significant effect. Due to refractory hyperlipidemia, regular therapeutic apheresis (1–3 procedures per month; 62 sessions by July 2025) was initiated on December 22, 2022, which resulted in acute decreases in total cholesterol and LDL-cholesterol by 40–70% after each procedure. Significant regression of xanthomatosis, a decrease in the intima-media thickness of the common carotid arteries, coronary artery stabilization, and achievement of target blood pressure values were observed. This case stresses the utmost importance of early routing of patients, family screening, and combined treatment with high-intensity pharmacotherapy and regular lipoprotein apheresis to reduce cholesterol deposits on any part of the body in patients with impaired mechanisms of clearance of cholesterol and to stabilize vascular changes in children with HoFH.
small molecules
2026-08-01 | Lipoprotein apheresis: still needed in many patients, or soon a historical practice?
Abstract Lipoprotein apheresis (LA) has long been used as an ultima ratio therapy for patients with extreme lipid-driven cardiovascular risk. One perspective maintains that, despite major advances in lipid-lowering pharmacology and the emergence of gene-silencing therapies, LA remains indispensable for selected patients with homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia refractory to maximal therapy, and isolated lipoprotein(a) [Lp(a)]–mediated progressive cardiovascular disease. An opposing view argues that modern and emerging pharmacological agents—PCSK9 inhibitors, inclisiran, bempedoic acid, evinacumab, and targeted Lp(a)-lowering antisense and small interfering RNA (siRNA) agents—have already rendered LA obsolete in almost all patients, with its remaining niche closing rapidly as outcome data accumulate. This combined manuscript juxtaposes the two positions in a streamlined form and concludes with a balanced conclusion of the future role of LA.
2026-05-01 | Triazine Thiols Decrease Apolipoprotein B Secretion From Hepatocytes Through Inhibition of Human Carboxylesterase 1.
Homozygous familial hypercholesterolemia is an autosomal genetic disorder that generates increased levels of low-density lipoproteins in the serum. Elevated low-density lipoprotein results in hypercholesterolemia leading to potentially fatal cardiovascular disease. Patients with homozygous familial hypercholesterolemia are often refractory to standard cholesterol-lowering treatments. Some available pharmaceuticals developed specifically for homozygous familial hypercholesterolemia can elevate hepatic lipid levels and in other cases have limited accessibility. Previously, we identified a family of triazine thiol compounds that effectively reduce apolipoprotein B-100 secretion by hepatocytes. In mice with humanized livers, triazine thiols effectively lowered serum cholesterol, triglycerides, low-density lipoproteins and lipoprotein(a). Despite their effectiveness, the mode of action of triazine thiols was unknown. Affinity-based mass spectrometry, biochemical assays, molecular modeling, and gene-edited induced pluripotent stem cell-derived hepatocyte-like cells were used to identify and characterize the molecular target and mechanism of action of triazine thiols. Using affinity-based mass spectrometry, we identified Carboxylesterase 1 (CES1) as a triazine thiol binding protein. Biochemical assays demonstrated that triazine thiols are slow-binding, allosteric, covalent CES1-specific inhibitors. Molecular modeling identified a predicted binding site within CES1 near cysteine 390, and loss of this cysteine conferred resistance to triazine thiol-mediated inhibition. Moreover, hepatocyte-like cells derived from CES1-/- induced human pluripotent stem cells exhibited a significant reduction in APOB secretion, mimicking the effect of triazine thiol treatment. This study establishes triazine thiols as novel, highly specific carboxylesterase 1 inhibitors, providing insight into their mechanism and highlighting carboxylesterase 1 inhibition as an approach for treating hypercholesterolemia.
2026-02-14 | The evolving therapeutic landscape of PCSK9 inhibition.
Cardiovascular disease remains the leading cause of death worldwide with low density lipoprotein being a major, yet modifiable, risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in regulating low density lipoprotein (LDL) receptor expression. Naturally occurring loss-of-function variants in the PCSK9 gene result in lifelong lower LDL cholesterol (LDL-C) levels and significantly lower risk of atherosclerotic cardiovascular disease (ASCVD), providing strong genetic validation of PCSK9 as a therapeutic target. This insight has driven the development of therapies directed at PCSK9 for the management of hypercholesterolaemia, particularly in patients who fail to meet LDL-C targets despite maximally tolerated statin and ezetimibe. This is especially the case for patients who are statin intolerant or who have homozygous or heterozygous familial hypercholesterolaemia. The field has progressed rapidly from monoclonal antibodies to small interfering RNA and oral therapies, with gene editing strategies offering a potentially permanent inhibition of PCSK9. This review summarizes the evidence supporting the currently approved PCSK9 inhibitors. We discuss some novel therapies that are currently in development and consider some expanding indications for PCSK9 inhibition.
2026-02-02 | Where lipoproteins meet T cells: LDL receptor in the growing landscape of immune modulation
T cells are highly adaptable immune cells that play a central role in host defense against infections, malignancies, and other threats. For effective immune responses, T cells must rapidly switch from a resting state to an active, energy-demanding state after recognizing antigen, and subsequently return to a quiescent state once the threat has been cleared. Tight regulation of this dynamic process is essential for immune homeostasis, as uncontrolled or prolonged T cell activation can result in chronic inflammation, tissue damage, or the development of autoimmune disease. T cell function is closely linked to intracellular metabolism. Nutrient uptake and energy metabolism are now recognized as key determinants of T cell activation, differentiation, and function. Within this context, the role of lipid metabolism, and specifically the use of lipoproteins by T cells, remains incompletely understood. Lipoproteins are the primary transporters for lipids such as cholesterol and triglycerides in the circulation. Low-density lipoprotein (LDL) delivers cholesterol to peripheral tissues, where it is essential for membrane synthesis, hormone production, and cellular growth. Cellular LDL uptake is largely mediated by the LDL receptor (LDLR), which is expressed by many cell types, including immune cells. Despite the fundamental importance of this pathway, its role in T cell biology has remained poorly characterized. This thesis investigates whether T cell responses can be modulated through manipulation of lipoprotein uptake and metabolism. Chapter 2 establishes a conceptual framework by introducing the field of immunometabolism, outlining how metabolic pathways and nutrient availability shape immune cell behavior, and highlighting their relevance in chronic inflammatory diseases such as atherosclerosis and cancer. Chapter 3 uncovers an immunological role for lipoproteins as carriers of lipid antigens, showing that circulating lipoproteins can transport lipid antigens to invariant natural killer T (iNKT) cells and induce their activation. Chapters 4 and 5 further delineate the role of LDLR-dependent lipoprotein uptake in CD4+ and CD8+ T cell subsets. Using cells derived from patients with homozygous familial hypercholesterolemia (hoFH), with mutations in the LDLR, this work demonstrates the importance of LDLR-mediated lipoprotein uptake in T cell function. LDLR-mediated uptake shaped CD4+ T cell activation, proliferation, and differentiation, particularly promoting the development of IL-10-producing immunoregulatory CD4+ T cells. In CD8+ T cells, PCSK9-mediated downregulation of LDLR impaired activation and effector function, whereas pharmacological inhibition of PCSK9 restored cytotoxic capacity, revealing opportunities to repurpose cholesterol-lowering therapies to enhance cancer immunotherapy. Chapter 6 explores strategies to improve tumor antigen presentation by increasing MHC class I expression, thereby enhancing CD8+ T cell-mediated tumor recognition. Finally, Chapter 7 emphasizes the metabolic flexibility of T cells, underscoring the therapeutic potential and complexity of targeting interconnected metabolic networks to modulate immune responses. Together, these findings establish lipoprotein metabolism as a key modulator of T cell immunity and underscore metabolic pathways as promising, though complex, targets for therapeutic intervention.
2026-01-21 | Severe hypercholesterolemia in a pediatric cohort: Familial homozygous and autosomal recessive hypercholesterolemia.
Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premature cardiovascular disease (CVD). Our study aims to describe and compare the clinical, biochemical, and genetic profiles of pediatric patients diagnosed with FH based on LDL-C levels exceeding 400 mg/dL (10.4 mmol/L) and confirmed by biallelic pathogenic variants in low-density lipoprotein receptor (LDLR) or low-density lipoprotein receptor adapter protein-1 (LDLRAP1) genes. This retrospective cohort study included 39 pediatric patients diagnosed with FH at a tertiary care center. Clinical data were analyzed, including age at diagnosis, family history, lipid profile, presence of xanthomas, and cardiovascular complications. Molecular analysis was conducted using next-generation sequencing (NGS) and Sanger sequencing to confirm pathogenic variants. Statistical comparisons were performed between the LDLR and LDLRAP1 variant groups regarding lipid profiles, treatment response, and cardiovascular outcomes. Among 39 patients, 32 and 7 had pathogenic variants in LDLR and LDLRAP1 genes, respectively. Genetic analysis identified 27 unique pathogenic variants in LDLR (including 5 novel mutations) and 4 in LDLRAP1 causal for autosomal recessive hypercholesterolemia (ARH), highlighting the molecular diversity of FH. Compared to the LDLR variant group, LDLRAP1 variant patients had significantly lower untreated LDL-C levels (640.0 ± 155.6 mg/dL [16.6 ± 4.0 mmol/L] vs 506.9 ± 130.1 mg/dL [13.1 ± 3.4 mmol/L], P = .026] and showed a superior response to lipid-lowering therapy (LLT), with a greater percentage (70.6% ± 12.0%) reduction in LDL-C levels (P = .015). While xanthomas were present in 62.5% of LDLR variant patients, they were less frequent (42.9%) in the LDLRAP1 group (P = .107). Cardiovascular complications were observed exclusively in LDLR variant patients. Fourteen patients required lipoprotein apheresis (LA), and one underwent liver transplantation due to severe aortic stenosis. This study highlights the importance of genetic testing in differentiating classical semidominant homozygous FH from ARH, given their phenotypic overlap but distinct treatment responses. LDLRAP1 variant patients with ARH exhibit better LDL-C reductions with conventional LLT, suggesting a milder phenotype. Early diagnosis, aggressive LLT, and novel treatments are essential to mitigate cardiovascular risk. Future studies with larger cohorts and long-term follow-ups are needed to refine treatment strategies for pediatric FH.
gene therapies
2026-07-18 | Precise hepatic base editing of ASGR1 enables robust and durable LDLR-independent lipid lowering in vivo.
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-cholesterol (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.
2026-06-25 | A de novo LDLR mutation in severe familial hypercholesterolemia: case report, functional characterization, and a personalized gene correction strategy exploration.
Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by elevated plasma low-density lipoprotein resulting in cardiovascular disease (CVD). The harmful mutations of LDLR are the main cause of FH. Especially, there is no effective treatment options for homozygous FH (HoFH) patients. Numerous FH cases have been reported, but most mutations remain unvalidated and lack gene correction studies. The study aims to assess the pathogenicity of a novel mutation, LDLR c.331C>T (p.Gln111Ter), and seek its gene correction strategy. The study systematically evaluated a female HoFH patient and her family. Using CRISPR/Cas9 technology, a Huh7 cell line carrying the point mutation was constructed. The impact of this mutation on LDLR protein expression was confirmed by qPCR, Western blot (WB), and immunofluorescence. A high-fidelity gene correction system targeting the LDLR c.331C>T point mutation was established based on the prime editing (PE) technology. The HoFH patient exhibited a biallelic LDLR mutation comprising an LDLR c.1693_1696 del GGCA inherited from her mather and a de novo LDLR c.331C>T (p.Gln111Ter) mutation. In vitro validation indicated that the mutation impaired normal LDLR protein expression, and the candidate gene editing system achieved approximately 98% correction efficiency. LDLR c.331C>T is a likely pathogenic mutation, which canbe precisely corrected by PE technology. The study expands the spectrum of likely pathogenic mutations in FH and holds promise for personalized, precise gene therapy through customized therapeutic systems, potentially alleviating or curing HoFH-a current challenge in conventional clinical management.
2026-06-09 | Table 1_A de novo LDLR mutation in severe familial hypercholesterolemia: case report, functional characterization, and a personalized gene correction strategy exploration.docx
Background Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by elevated plasma low-density lipoprotein resulting in cardiovascular disease (CVD). The harmful mutations of LDLR are the main cause of FH. Especially, there is no effective treatment options for homozygous FH (HoFH) patients. Numerous FH cases have been reported, but most mutations remain unvalidated and lack gene correction studies. The study aims to assess the pathogenicity of a novel mutation, LDLR c.331C>T (p.Gln111Ter), and seek its gene correction strategy. Methods The study systematically evaluated a female HoFH patient and her family. Using CRISPR/Cas9 technology, a Huh7 cell line carrying the point mutation was constructed. The impact of this mutation on LDLR protein expression was confirmed by qPCR, Western blot (WB), and immunofluorescence. A high-fidelity gene correction system targeting the LDLR c.331C>T point mutation was established based on the prime editing (PE) technology. Results The HoFH patient exhibited a biallelic LDLR mutation comprising an LDLR c.1693_1696 del GGCA inherited from her mather and a de novo LDLR c.331C>T (p.Gln111Ter) mutation. In vitro validation indicated that the mutation impaired normal LDLR protein expression, and the candidate gene editing system achieved approximately 98% correction efficiency. Conclusion LDLR c.331C>T is a likely pathogenic mutation, which canbe precisely corrected by PE technology. The study expands the spectrum of likely pathogenic mutations in FH and holds promise for personalized, precise gene therapy through customized therapeutic systems, potentially alleviating or curing HoFH—a current challenge in conventional clinical management.
2026-04-17 | Severe polyarterial involvement in a 16-year-old with homozygous familial hypercholesterolaemia: a case report.
Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by an elevated plasma concentration of low-density lipoprotein cholesterol (LDL-C) starting at birth and a significantly increased risk of premature atherosclerotic cardiovascular disease. We report the case of a 16-year-old female patient, with no known consanguinity, presented to our cardiology department for anginal chest pain on exertion associated with headaches. She presented with characteristic morphological features of FH. Her lipid profile revealed extremely high LDL-C levels (706 mg/dL) and such extensive arterial and cutaneous involvement. This case underscores the importance of recognizing xanthomas and their association with an increased risk of coronary atherosclerosis.
2026-02-26 | Hepatocyte-Specific Knockout of YAP Protects Against Atherosclerosis via Inhibition of ANGPTL3 in Mice.
Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Hyperlipidemia models were generated in apoE knockout (apoE-/-) mice or mice injected with adeno-associated virus 8-D377Y-mPCSK9, which degrades and deletes LDLR (low-density lipoprotein receptor), by being fed a high-cholesterol diet for 12 weeks. We measured the expression level of hepatic YAP in these apoE-/- mice. Next, we created YAPΔHep (hepatocyte-specific deletion of Yes-associated protein) apoE-/- mice to further determine the role of YAP in hyperlipidemia and atherosclerosis. AML12 (alpha mouse liver 12) cells and mice injected with AAV8-D377-mPCSK9 (adeno-associated virus 8 carrying the D377Y mutant of mouse proprotein convertase subtilisin/kexin type 9) or YAPΔHepapoE-/- mice were used to elucidate its mechanism. Finally, apoE-/- or LDLR knockout (LDLR-/-) mice were used to observe the therapeutic efficacy of adeno-associated virus 8-Alb (albumin)-shYAP (short hairpin RNA targeting for YAP) for hyperlipidemia and atherosclerosis. High-cholesterol diet-fed apoE-/- mice showed increased levels of YAP in the liver. Further investigation indicated that YAPΔHepapoE-/- mice exhibited lighter hyperlipidemia and atherosclerosis than YAPflox/floxapoE-/- mice fed with a high-cholesterol diet. Conversely, hepatocyte-specific overexpression of YAP (5S) deteriorated hyperlipidemia and atherosclerosis in high-cholesterol diet-fed apoE-/- mice. Furthermore, the lipid-lowering effect of YAP deficiency in hepatocytes was independent of LDLR. Hepatocyte-specific overexpression of ANGPTL3 (angiopoietin-like 3) aggravated hyperlipidemia and atherosclerosis in YAPΔHepapoE-/- mice, indicating that ANGPTL3 is responsible for the function of YAP in hyperlipidemia. Mechanistically, YAP upregulated ANGPTL3 via TEAD (TEA domain family member) 4 in hepatocytes independent of LDLR. Notably, adeno-associated virus 8-Alb-shYAP lowered lipid levels in apoE-/- or LDLR-/- mice. Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia.
antibodies
2026-07-12 | The Angiopoietin-like Protein (ANGPTL) Axis in Dyslipidemia: Mechanisms, Cardiovascular Risk, and Emerging Therapies.
The angiopoietin-like protein (ANGPTL) 3-4-8 axis has emerged as a central regulator of lipoprotein lipase and lipid metabolism. This review examines the mechanistic basis of ANGPTL pathway modulation and therapeutic implications for cardiovascular risk reduction across diverse phenotypes of dyslipidemia. Genetic studies demonstrate that loss-of-function variants in ANGPTL3 and ANGPTL4 are associated with lower triglycerides and decreased coronary artery disease risk. Pharmacologic inhibition of ANGPTL3 with monoclonal antibodies and RNA-based therapies reduces triglycerides, remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) through mechanisms predominantly independent of the LDL receptor. Clinical trials with ANGPTL3 inhibitors have demonstrated marked LDL-C reductions in patients with homozygous familial hypercholesterolemia (HoFH), as well as broad lipid-lowering effects in patients with mixed dyslipidemia. Emerging strategies targeting the ANGPTL3/8 complex and ANGPTL4 further refine lipid-lowering effects, while early genome-editing data suggest the potential for durable ANGPTL3 suppression. Modulation of the ANGPTL-lipoprotein lipase axis is a novel strategy to address residual atherosclerotic risk beyond traditional LDL receptor-dependent therapies. ANGPTL3 inhibitors have been practice-changing in HoFH, and more broadly, ANGPTL-directed therapies hold promise for patients with mixed dyslipidemia to mitigate cardiovascular risk.
2026-07-02 | Homozygous familial hypercholesterolemia, experience with Evinacumab treatment in two Mexican pediatric patients: case report
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.
2026-06-24 | Management of autosomal recessive hypercholesterolemia in a patient with an LDLRAP1 mutation.
Familial hypercholesterolemia (FH) is characterized by a lifelong elevation of low-density lipoprotein cholesterol (LDL-C), conferring an increased risk of premature atherosclerotic disease and its associated burden of morbidity and mortality. Autosomal recessive hypercholesterolemia (ARH) is a rare form of homozygous FH (HoFH) and is a distinct subset caused by mutations in the low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene. We present a 29-year-old South Asian male who visited the lipid clinic with a markedly elevated, untreated LDL-C level of 557 mg/dL. Clinical and genetic evaluation identified a homozygous pathogenic splice donor variant in the LDLRAP1 (c.344+1G>A), confirming the diagnosis of ARH. On examination, a grade III/VI systolic ejection murmur was appreciated, prompting further investigation that confirmed mild aortic stenosis. Achieving adequate LDL-C control for this patient required stepwise escalation of the lipid-lowering therapy comprising high-intensity statin therapy, proprotein convertase subtilisin/kexin type 9 inhibitor, bempedoic acid, and ultimately evinacumab. This case draws attention to the importance of appropriately diagnosing and treating individuals with ARH and initiating combination lipid-lowering therapy, including specialty medications indicated for this diagnosis, to effectively treat this disorder, as well as the importance of screening for valvular heart disease in this population.
2026-05-15 | EVINACUMAB, A NEW TREATMENT FOR FAMILIAL HYPERCHOLESTEROLAEMIA: MECHANISM OF ACTION, SAFETY AND EFFICACY
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels and a markedly increased risk of premature atherosclerotic cardiovascular disease. The aim of this review was to summarize current knowledge on the pathophysiology, diagnosis, and management of HoFH, with particular emphasis on angiopoietin-like protein 3 (ANGPTL3) inhibition and the clinical role of evinacumab. A comprehensive analysis of published clinical trials, guidelines, and observational studies was conducted to evaluate available diagnostic criteria and therapeutic strategies. Standard lipid-lowering therapies often fail to achieve recommended LDL-C targets in HoFH due to impaired LDL receptor function. Evinacumab, a fully human monoclonal antibody targeting ANGPTL3, has demonstrated substantial LDL-C reductions independent of LDL receptor activity in both adult and pediatric patients. Clinical studies report LDL-C reductions of approximately 45–50%, along with a favorable safety profile. In conclusion, ANGPTL3 inhibition with evinacumab represents a significant advancement in the treatment of HoFH, offering an effective therapeutic option for patients with inadequate response to conventional lipid-lowering therapies.
2026-05-07 | Promise of ANGPTL3 as a therapeutic target for controlling cholesterol levels.
Angiopoietin-like protein 3 (ANGPTL3) has emerged over the past decade as one of the most intriguing therapeutic targets in lipid metabolism. Genetic deficiency of ANGPTL3 in humans produces a striking pan-hypolipidemic phenotype, with reductions in triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), accompanied by protection from atherosclerotic cardiovascular disease (ASCVD). These observations rapidly catalyzed the development of pharmacologic strategies to inhibit ANGPTL3 using monoclonal antibodies (e.g. evinacumab), antisense oligonucleotides (e.g. vupanorsen), small interfering ribonucleic acid (e.g. zodasiran and solbinsiran), and most recently genome-editing approaches (e.g. VERVE-201 and CTX310). However, clinical experience has revealed a more complex and context-dependent biology than initially anticipated. This review examines whether ANGPTL3 should be considered a clinically meaningful cholesterol-lowering target, as exemplified by efficacy of ANGPTL3 inhibition in homozygous familial hypercholesterolemia, or whether its principal therapeutic value lies in modulation of triglyceride-rich lipoproteins and remnant cholesterol, with secondary effects on LDL-C. The degree of hypertriglyceridemia in the patient's baseline lipid profile appears to be an important determinant of drug response. Drawing on genetic, mechanistic, and clinical trial data, the promise and limitations of ANGPTL3 inhibition are considered and its potential place in future lipid-lowering strategies is outlined.
other
2026-06-04 | New and Emerging Therapeutic Targets for ApoB-Containing Particles Lowering.
ApoB is the structural protein of all atherogenic lipoproteins, including VLDLs (very-low-density lipoproteins), IDLs (intermediate-density lipoproteins), LDLs (low-density lipoproteins), chylomicron remnants, as well as Lp(a) (lipoprotein[a]). Because each lipoprotein particle contains a single apoB molecule, plasma apoB concentration reflects the number of circulating atherogenic particles. Genetic, epidemiological, and randomized clinical trial evidence consistently demonstrate that, on a per-particle basis, apoB is a more accurate causal determinant of atherosclerotic cardiovascular disease risk than LDL cholesterol alone. Beyond atherosclerosis, apo B48-containing chylomicrons play a central role in severe hypertriglyceridemia and, importantly, contribute to the risk of triglyceride-mediated acute pancreatitis. Most established therapies that reduce major cardiovascular events, including statins, ezetimibe, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, and bempedoic acid, act primarily by enhancing LDL receptor-mediated clearance of apoB-containing particles. Other currently available therapies reduce LDL cholesterol as well as apoB through LDL receptor-independent mechanisms. Lomitapide, an inhibitor of MTP (microsomal triglyceride transfer protein), and evinacumab, a monoclonal antibody targeting ANGPTL3 (angiopoietin-like protein 3), reduce LDL cholesterol in homozygous familial hypercholesterolemia by decreasing triglyceride-rich apoB-containing lipoproteins upstream of LDL particle formation. Emerging therapeutic strategies targeting the angiopoietin-like protein axis, apo CIII, Lp(a), CETP (cholesteryl ester transfer protein), hepatic lipid flux, and incretin signaling expand the therapeutic landscape for modulating apoB-containing lipoproteins. Gene-targeted approaches, including gene editing, epigenome editing, small interfering RNA, and antisense oligonucleotides, as well as novel oral or injectable agents and combination therapies, further broaden opportunities for durable apoB modulation. Transitioning from an LDL cholesterol-centric to an apoB-centric framework may represent a biologically integrated strategy to reduce both atherosclerotic cardiovascular disease and triglyceride-mediated pancreatitis risk.
2026-02-28 | Variable phenotype associated with compound LDLR gene mutations in familial hypercholesterolemia patients: Case series and clinical implications.
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder with an extremely elevated level of low-density lipoprotein (LDL) cholesterol (LDL-C) and accelerated premature coronary artery disease (PCAD). It is primarily caused by a single pathogenic variant of the LDL receptor (LDLR) gene. This report presents 2 rare and unrelated cases of HoFH with compound LDLR mutations. These 2 individuals presented with atypical clinical features and demonstrated variable degrees of hypercholesterolemia. Case 1 is a 36-year-old Malay woman identified during family cascade screening with a pretreated LDL-C of 8.5 mmol/L and a strong family history of PCAD. Case 2 is a 58-year-old Indian woman discovered to have a pretreated LDL-C of 5.2 mmol/L during routine health screening, without a significant family history of hypercholesterolemia or PCAD. Neither patient demonstrated tendon xanthomas or other lipid stigmata. Both patients underwent lipid profiling and targeted next-generation sequencing of FH-related genes (LDLR, APOB, PCSK9, ABCG5, and ABCG8). Two novel LDLR variants were identified in exon 18: c.2548-1_2548delGAinsTC (pathogenic) and c.2556_2557insTCAGTCTGG (p.Leu853Serfs*12; likely pathogenic) and classified according to American College of Medical Genetics and Genomics guidelines. Case 1 was homozygous for both variants, while Case 2 was homozygous for the splice-site variant and heterozygous for the frameshift variant. Both patients received guideline-directed lipid-lowering therapy and ongoing cardiovascular risk management. Despite biallelic LDLR variants, both patients demonstrated relatively milder hypercholesterolemia and absence of classical HoFH stigmata. The LDLR variants located in exon 18 affecting the cytoplasmic tail domain may be associated with attenuated clinical expression. Recognition of genotype-phenotype variability is crucial for accurate diagnosis, risk stratification, and individualized management of HoFH.
2026-02-14 | A nationwide genetic and phenotypic spectrum of 63 probands of homozygous familial hypercholesterolemia in Taiwan.
The genetic and phenotypic spectrum of homozygous familial hypercholesterolemia (HoFH) in Han Chinese populations remains insufficiently defined. To delineate the nationwide genetic and clinical features of HoFH in Taiwan, including true HoFH, double heterozygous FH (HeFH), and compound HeFH. Patients with clinically diagnosed probable or definite FH enrolled in the Taiwan FH Registry who underwent genetic testing between 2006 and 2025 were analyzed. A comprehensive workflow integrating microarray assay, mass spectrometry, targeted next-generation sequencing, and multiplex ligation-dependent probe amplification was implemented. Variants were classified using American College of Medical Genetics and Genomics guidelines. Of 1479 screened individuals, 63 were genetically confirmed to have HoFH (mean age, 32.8 ± 22.7 years), including 28.6% with atherosclerotic vascular disease. The cohort comprised 14 true HoFH (including homozygous APOB variants), 6 double HeFH, and 43 compound HeFH. The highest documented low-density lipoprotein cholesterol (LDL-C) levels were 357.3 ± 123.5 mg/dL in true HoFH, 347.3 ± 39.2 mg/dL in double HeFH, and 443.5 ± 170.9 mg/dL in compound HeFH. The most frequent genotypes were LDLR [IVS2+4A>T];[IVS2+4A>T] in true HoFH, [APOB p.R3527W];[LDLR IVS2+4A>T] and [APOB p.R3527W];[LDLR p.D90N] in double HeFH, and LDLR [p.D90N];[p.C329Y] in compound HeFH. Patients with double HeFH had lower LDL-C levels and fewer xanthomas than those with LDLR homozygosity or compound mutations, while individuals with homozygous LDLR exon deletions/duplications had the highest LDL-C levels. This nationwide study provides the first comprehensive genetic and clinical characterization of HoFH in Taiwan. Our findings highlight the importance of precise genetic diagnosis and early detection strategies in improving outcomes for this high-risk population.
2025-11-03 | Abstract 4365849: Selective Degradation of Excess Free Cholesterol in the Liver by REP-0003 Regresses Atherosclerotic Plaque in Ldlr -/- Mice: A Novel Approach for HoFH
Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR ) gene, leading to severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. In HoFH patients, statins and PCSK9 inhibitors are ineffective and, while new lipid-lowering therapies including angiopoietin-like 3 inhibitors and lomitapide offer hope, they have not been shown to effectively regress existing plaque, highlighting a critical unmet medical need. The Cholesterol Degrading Platform (CDP) is a fusion protein that degrades excess intracellular free cholesterol into a non-toxic, excretable catabolite to safely regress cholesterol-rich vulnerable plaque. We propose that excess free cholesterol from hypercholesterolemia impairs mechanisms that can otherwise regress atherosclerotic plaque, and that the selective degradation of this free cholesterol in the liver will restore liver health and promote plaque regression throughout the systemic circulation. Methods: Ldlr -/- mice ( n=96 ) were fed a Western diet for 16 weeks and randomized based on body weight and time to exhaustion on an inclined (10%) treadmill. Mice received either intravenous phosphate buffered saline (PBS; equal volume/kg, qw) or REP-0003 (LNP- CDP mRNA ; 0.05–1.50 mg/kg, qw) for 6 weeks followed by another treadmill exhaustion test. At euthanasia, tissues and blood were harvested and assessed for blood chemistries, serum biomarkers, atherosclerotic plaque burden, and histopathology. Results: Compared with PBS, REP-0003 treatment significantly reduced serum alanine transaminase (ALT) levels by 40.5 ± 3.7% ( P<0.01 , indicating improved liver health), reduced serum ApoB levels by 23.9 ± 1.0% ( P<0.01 ) and increased HDL free cholesterol fraction by 61.2 ± 5.8% ( P<0.01 ). Versus controls, (a) aortic root plaque cross-sectional area and aortic tree plaque count/area were significantly reduced by 27.2 ± 4.8% ( P<0.01 ) and 25.8 ± 1.8% ( P<0.05 ), respectively, (b) plaque macrophage infiltration via CD68 staining significantly decreased by 61.5 ± 11.4% ( P<0.01 ), and (c) treadmill runtime significantly increased by 67.2 ± 6.5% ( P<0.01 ). Conclusion: REP-0003 therapy specifically degrades excess free cholesterol in the liver to safely and effectively reduce atherosclerotic plaque burden and enhance exercise tolerance in Ldlr -/- mice, offering a promising first-in-class therapeutic approach for HoFH-associated atherosclerosis.
2024-12-13 | An up-to-date review of emerging biologic therapies for hypercholesterolemia.
Hypercholesterolemia and other lipid disorders are major causes of atherosclerotic cardiovascular disease (ASCVD). Statins have been the mainstay of lipid-lowering therapy for many years, but they may not be adequate to achieve the target low-density lipoprotein (LDL) cholesterol levels and there are other residual lipid risk factors. This article reviews the biologic therapies in development for hypercholesterolemia identified by a PubMed search. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a major focus, but the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3) that were originally developed to reduce the levels of triglyceride-rich lipoproteins are now being explored to reduce cardiovascular events in a wider range of patients. A brief overview of biologic therapies targeting lipoprotein(a) [Lp(a)] is also proved. Inhibition of PCSK9 remains an attractive target. In addition to the currently available monoclonal antibodies (mAbs) and small interfering RNA (siRNA), new mAbs and the adenectin lerodalcibep are promising therapies. The antisense oligonucleotide (ASO) and siRNA inhibitors of apoC3 and ANGPTL3 are effective in severe hypertriglyceridemia and homozygous familial hypercholesterolemia, respectively, and may prove to have wider applications. ASO and siRNA inhibitors of Lp(a) are currently in cardiovascular outcome studies.
cell therapies
2026-06-26 | Women with Homozygous Familial Hypercholesterolemia and Impact on Reproductive Life from Menarche to Menopause: Long-Term Case Series Observational Study
Homozygous familial hypercholesterolemia (HoFH) is a genetic disease in which LDL-C is high at birth, causing cardiovascular disease. Reproductive issues in women are also caused by lipid-lowering therapies (LLTs) that must be interrupted during pregnancy and breastfeeding. The only safe choice during pregnancy is lipoprotein apheresis (LA), although there are limited data regarding fertility, pregnancy, and menopause. This long-term case series observational study examined 23 genetically confirmed HoFH women in a tertiary health facility, obtaining clinical, cardiovascular, biochemical, and reproductive information through medical records and structured interviews. Cardiovascular disease and aortic valve disease were found in 48% and 52%, respectively; four women died prematurely. Menarche (12.1 years) and menopause (52.0 years) were in the normal range. The majority of these had regular menstrual cycles; there was one case of polycystic ovary syndrome. Twelve women became spontaneously pregnant. Obstetric complications included preterm delivery, gestational diabetes, hypertension, and fetal growth restriction. This study showed that continuous LA during pregnancy was associated with better lipid control and maternal-fetal outcomes, but cardiovascular impairment was observed in the case of interruption of LLT. LLT interruption affects the inherited lipid disorder, and a very short period of breastfeeding is recommended. HoFH in women under treatment has no impact on the menstrual cycle or on the timing of menopause. Pregnancy is a high-risk condition that needs the care of a multidisciplinary team. The need to ensure continuous LA, systematic reproductive counseling, early cardiovascular examination, and aligned lifelong care is critical in maximizing the outcome of HoFH women.
2026-06-24 | Synergistic "targeting and blockade" strategy via engineered exosomes and clinical ultrasound contrast agent for hepatocyte-targeted mRNA delivery.
Homozygous familial hypercholesterolemia (HoFH) presents a persistent and difficult-to-treat condition. This recalcitrance stems largely from loss-of-function mutations within the low-density lipoprotein receptor (LDLR) gene, which severely undermine the efficacy of standard therapeutic regimens. Here, we report a bioinspired "targeting and blockade" strategy for the efficient delivery of functional Ldlr mRNA to hepatocytes. This approach is realized through a rationally designed platform, Szd + AP@ExoE-Ldlr, which integrates APOA1-functionalized exosomes for hepatocyte-targeted delivery with a preemptive macrophage blockade using the clinical ultrasound contrast agent Sonazoid (Szd). The APOA1 modification confers specific recognition by the scavenger receptor class B type 1 on hepatocytes, while the pre-saturation of Kupffer cells with Szd significantly mitigates nonspecific clearance by the mononuclear phagocyte system (MPS). In a HoFH murine model, this synergistic strategy markedly enhanced the accumulation of exosomes in hepatocytes and achieved robust restoration of hepatic LDLR expression. Consequently, it elicited a profound correction of the atherogenic lipid profile and substantially attenuated the progression of atherosclerosis. A comprehensive biosafety evaluation confirmed the excellent biocompatibility of this platform. Our work provides a promising and broadly applicable solution for the treatment of liver-related genetic disorders by simultaneously overcoming the critical barriers of targeted delivery and MPS evasion.
2026-04-17 | Liver transplantation in severe homozygous familial hypercholesterolaemia: a scoping review.
Liver transplantation is the only known potentially curative treatment for homozygous familial hypercholesterolaemia (HoFH). While this procedure often normalises low-density lipoprotein cholesterol (LDL-C) levels and can reverse coronary atherosclerosis and regress xanthomata, its long-term risks and benefits remain elusive. The purpose of this review was to examine the extant literature on the safety and efficacy of liver transplantation in patients with HoFH. A scoping review was conducted for relevant literature primarily focused on safety (e.g. surgical complications, rejection, immunosuppressive therapy, mortality) and effectiveness outcomes (e.g. serum LDL-C levels, xanthoma changes, atherosclerotic cardiovascular disease or events) of liver transplantation in severe HoFH. The PRISMA-ScR guideline was followed. We searched five databases (Medline, Embase, Global Health, Web of Science and CINAHL) from inception to September 2025. A total of 76 studies and 212 cases were included. The majority (53%) of studies were case reports. Liver transplantation was done mostly in children, genetically or phenotypically diagnosed with HoFH. The median follow-up time for individuals was 3.5 years. While the effectiveness of liver transplantation with reference to LDL-C reduction and xanthomata regression were well documented, long-term outcomes such as cardiovascular events and mortality were not consistently reported. While liver transplantation holds great potential for normalising circulatory LDL-C levels in patients with HoFH, due to the rare nature of HoFH, the current literature remains incomplete concerning its safety and efficacy. To fill this gap, future efforts should utilise liver transplantation registries, to increase sample size and standardise longer-term follow-up.
2026-01-21 | Clinical and Subclinical Atherosclerotic Disease in Adolescents With Familial Hypercholesterolemia.
Familial hypercholesterolemia is primarily a disorder of reduced low-density lipoprotein (LDL) clearance, which can be inherited in either homozygous or heterozygous form. Despite the availability of various modalities to achieve target LDL cholesterol levels, inadequate control remains a significant risk factor for accelerated atherosclerosis in the pediatric population. Moreover, the occurrence of coronary artery disease in adolescents poses unique management challenges given the limited representation of this age group in clinical trials. We report 2 cases of coronary artery disease and 1 case of subclinical atherosclerosis in adolescent patients with genetically confirmed familial hypercholesterolemia, outlining the diagnostic work-up, challenges in achieving LDL cholesterol control, measures undertaken, including plasma exchange, and revascularization strategies using drug-eluting stents or drug-coated balloons, in accordance with current guidelines.
2025-12-01 | Homozygous familial hypercholesterolemia in a child: A clinical effect of regular lipoprotein apheresis in a multispecialty children’s hospital
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited condition associated with extremely elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), leading to early vascular atherosclerosis. Here we report a clinical observation of a girl with early-onset multiple xanthomatosis (the age of clinical symptom onset was 1.5 years) and a genetically confirmed homozygous variant, c.1729T>C, in the LDLR gene (p.W577R). The diagnosis was established at the age of 3 (TC up to 25 mmol/L; TC level time profile remained at 23.5 mmol/L, LDL-C 22.1 mmol/L). However, a targeted lipidlowering diet was not arranged in a consistent manner, and the drug therapy was not conducted, which reflected physicians' poor awareness and lack of routing of patients. The patient has been followed at the Z. A. Bashlyaeva Children's City Clinical Hospital of the Moscow Health Department (Competence Center for Screening and Treatment of Lipid Disorders in Children and Adolescents) since the age of 6.5 years. All attempts to choose any beneficial combination lipid-lowering pharmacotherapy (rosuvastatin, ezetimibe, evolocumab) have not yielded a clinically significant effect. Due to refractory hyperlipidemia, regular therapeutic apheresis (1–3 procedures per month; 62 sessions by July 2025) was initiated on December 22, 2022, which resulted in acute decreases in total cholesterol and LDL-cholesterol by 40–70% after each procedure. Significant regression of xanthomatosis, a decrease in the intima-media thickness of the common carotid arteries, coronary artery stabilization, and achievement of target blood pressure values were observed. This case stresses the utmost importance of early routing of patients, family screening, and combined treatment with high-intensity pharmacotherapy and regular lipoprotein apheresis to reduce cholesterol deposits on any part of the body in patients with impaired mechanisms of clearance of cholesterol and to stabilize vascular changes in children with HoFH.
small molecules
2026-08-01 | Lipoprotein apheresis: still needed in many patients, or soon a historical practice?
Abstract Lipoprotein apheresis (LA) has long been used as an ultima ratio therapy for patients with extreme lipid-driven cardiovascular risk. One perspective maintains that, despite major advances in lipid-lowering pharmacology and the emergence of gene-silencing therapies, LA remains indispensable for selected patients with homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia refractory to maximal therapy, and isolated lipoprotein(a) [Lp(a)]–mediated progressive cardiovascular disease. An opposing view argues that modern and emerging pharmacological agents—PCSK9 inhibitors, inclisiran, bempedoic acid, evinacumab, and targeted Lp(a)-lowering antisense and small interfering RNA (siRNA) agents—have already rendered LA obsolete in almost all patients, with its remaining niche closing rapidly as outcome data accumulate. This combined manuscript juxtaposes the two positions in a streamlined form and concludes with a balanced conclusion of the future role of LA.
2026-05-01 | Triazine Thiols Decrease Apolipoprotein B Secretion From Hepatocytes Through Inhibition of Human Carboxylesterase 1.
Homozygous familial hypercholesterolemia is an autosomal genetic disorder that generates increased levels of low-density lipoproteins in the serum. Elevated low-density lipoprotein results in hypercholesterolemia leading to potentially fatal cardiovascular disease. Patients with homozygous familial hypercholesterolemia are often refractory to standard cholesterol-lowering treatments. Some available pharmaceuticals developed specifically for homozygous familial hypercholesterolemia can elevate hepatic lipid levels and in other cases have limited accessibility. Previously, we identified a family of triazine thiol compounds that effectively reduce apolipoprotein B-100 secretion by hepatocytes. In mice with humanized livers, triazine thiols effectively lowered serum cholesterol, triglycerides, low-density lipoproteins and lipoprotein(a). Despite their effectiveness, the mode of action of triazine thiols was unknown. Affinity-based mass spectrometry, biochemical assays, molecular modeling, and gene-edited induced pluripotent stem cell-derived hepatocyte-like cells were used to identify and characterize the molecular target and mechanism of action of triazine thiols. Using affinity-based mass spectrometry, we identified Carboxylesterase 1 (CES1) as a triazine thiol binding protein. Biochemical assays demonstrated that triazine thiols are slow-binding, allosteric, covalent CES1-specific inhibitors. Molecular modeling identified a predicted binding site within CES1 near cysteine 390, and loss of this cysteine conferred resistance to triazine thiol-mediated inhibition. Moreover, hepatocyte-like cells derived from CES1-/- induced human pluripotent stem cells exhibited a significant reduction in APOB secretion, mimicking the effect of triazine thiol treatment. This study establishes triazine thiols as novel, highly specific carboxylesterase 1 inhibitors, providing insight into their mechanism and highlighting carboxylesterase 1 inhibition as an approach for treating hypercholesterolemia.
2026-02-14 | The evolving therapeutic landscape of PCSK9 inhibition.
Cardiovascular disease remains the leading cause of death worldwide with low density lipoprotein being a major, yet modifiable, risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in regulating low density lipoprotein (LDL) receptor expression. Naturally occurring loss-of-function variants in the PCSK9 gene result in lifelong lower LDL cholesterol (LDL-C) levels and significantly lower risk of atherosclerotic cardiovascular disease (ASCVD), providing strong genetic validation of PCSK9 as a therapeutic target. This insight has driven the development of therapies directed at PCSK9 for the management of hypercholesterolaemia, particularly in patients who fail to meet LDL-C targets despite maximally tolerated statin and ezetimibe. This is especially the case for patients who are statin intolerant or who have homozygous or heterozygous familial hypercholesterolaemia. The field has progressed rapidly from monoclonal antibodies to small interfering RNA and oral therapies, with gene editing strategies offering a potentially permanent inhibition of PCSK9. This review summarizes the evidence supporting the currently approved PCSK9 inhibitors. We discuss some novel therapies that are currently in development and consider some expanding indications for PCSK9 inhibition.
2026-02-02 | Where lipoproteins meet T cells: LDL receptor in the growing landscape of immune modulation
T cells are highly adaptable immune cells that play a central role in host defense against infections, malignancies, and other threats. For effective immune responses, T cells must rapidly switch from a resting state to an active, energy-demanding state after recognizing antigen, and subsequently return to a quiescent state once the threat has been cleared. Tight regulation of this dynamic process is essential for immune homeostasis, as uncontrolled or prolonged T cell activation can result in chronic inflammation, tissue damage, or the development of autoimmune disease. T cell function is closely linked to intracellular metabolism. Nutrient uptake and energy metabolism are now recognized as key determinants of T cell activation, differentiation, and function. Within this context, the role of lipid metabolism, and specifically the use of lipoproteins by T cells, remains incompletely understood. Lipoproteins are the primary transporters for lipids such as cholesterol and triglycerides in the circulation. Low-density lipoprotein (LDL) delivers cholesterol to peripheral tissues, where it is essential for membrane synthesis, hormone production, and cellular growth. Cellular LDL uptake is largely mediated by the LDL receptor (LDLR), which is expressed by many cell types, including immune cells. Despite the fundamental importance of this pathway, its role in T cell biology has remained poorly characterized. This thesis investigates whether T cell responses can be modulated through manipulation of lipoprotein uptake and metabolism. Chapter 2 establishes a conceptual framework by introducing the field of immunometabolism, outlining how metabolic pathways and nutrient availability shape immune cell behavior, and highlighting their relevance in chronic inflammatory diseases such as atherosclerosis and cancer. Chapter 3 uncovers an immunological role for lipoproteins as carriers of lipid antigens, showing that circulating lipoproteins can transport lipid antigens to invariant natural killer T (iNKT) cells and induce their activation. Chapters 4 and 5 further delineate the role of LDLR-dependent lipoprotein uptake in CD4+ and CD8+ T cell subsets. Using cells derived from patients with homozygous familial hypercholesterolemia (hoFH), with mutations in the LDLR, this work demonstrates the importance of LDLR-mediated lipoprotein uptake in T cell function. LDLR-mediated uptake shaped CD4+ T cell activation, proliferation, and differentiation, particularly promoting the development of IL-10-producing immunoregulatory CD4+ T cells. In CD8+ T cells, PCSK9-mediated downregulation of LDLR impaired activation and effector function, whereas pharmacological inhibition of PCSK9 restored cytotoxic capacity, revealing opportunities to repurpose cholesterol-lowering therapies to enhance cancer immunotherapy. Chapter 6 explores strategies to improve tumor antigen presentation by increasing MHC class I expression, thereby enhancing CD8+ T cell-mediated tumor recognition. Finally, Chapter 7 emphasizes the metabolic flexibility of T cells, underscoring the therapeutic potential and complexity of targeting interconnected metabolic networks to modulate immune responses. Together, these findings establish lipoprotein metabolism as a key modulator of T cell immunity and underscore metabolic pathways as promising, though complex, targets for therapeutic intervention.
2026-01-21 | Severe hypercholesterolemia in a pediatric cohort: Familial homozygous and autosomal recessive hypercholesterolemia.
Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premature cardiovascular disease (CVD). Our study aims to describe and compare the clinical, biochemical, and genetic profiles of pediatric patients diagnosed with FH based on LDL-C levels exceeding 400 mg/dL (10.4 mmol/L) and confirmed by biallelic pathogenic variants in low-density lipoprotein receptor (LDLR) or low-density lipoprotein receptor adapter protein-1 (LDLRAP1) genes. This retrospective cohort study included 39 pediatric patients diagnosed with FH at a tertiary care center. Clinical data were analyzed, including age at diagnosis, family history, lipid profile, presence of xanthomas, and cardiovascular complications. Molecular analysis was conducted using next-generation sequencing (NGS) and Sanger sequencing to confirm pathogenic variants. Statistical comparisons were performed between the LDLR and LDLRAP1 variant groups regarding lipid profiles, treatment response, and cardiovascular outcomes. Among 39 patients, 32 and 7 had pathogenic variants in LDLR and LDLRAP1 genes, respectively. Genetic analysis identified 27 unique pathogenic variants in LDLR (including 5 novel mutations) and 4 in LDLRAP1 causal for autosomal recessive hypercholesterolemia (ARH), highlighting the molecular diversity of FH. Compared to the LDLR variant group, LDLRAP1 variant patients had significantly lower untreated LDL-C levels (640.0 ± 155.6 mg/dL [16.6 ± 4.0 mmol/L] vs 506.9 ± 130.1 mg/dL [13.1 ± 3.4 mmol/L], P = .026] and showed a superior response to lipid-lowering therapy (LLT), with a greater percentage (70.6% ± 12.0%) reduction in LDL-C levels (P = .015). While xanthomas were present in 62.5% of LDLR variant patients, they were less frequent (42.9%) in the LDLRAP1 group (P = .107). Cardiovascular complications were observed exclusively in LDLR variant patients. Fourteen patients required lipoprotein apheresis (LA), and one underwent liver transplantation due to severe aortic stenosis. This study highlights the importance of genetic testing in differentiating classical semidominant homozygous FH from ARH, given their phenotypic overlap but distinct treatment responses. LDLRAP1 variant patients with ARH exhibit better LDL-C reductions with conventional LLT, suggesting a milder phenotype. Early diagnosis, aggressive LLT, and novel treatments are essential to mitigate cardiovascular risk. Future studies with larger cohorts and long-term follow-ups are needed to refine treatment strategies for pediatric FH.
gene therapies
2026-07-18 | Precise hepatic base editing of ASGR1 enables robust and durable LDLR-independent lipid lowering in vivo.
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-cholesterol (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.
2026-06-25 | A de novo LDLR mutation in severe familial hypercholesterolemia: case report, functional characterization, and a personalized gene correction strategy exploration.
Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by elevated plasma low-density lipoprotein resulting in cardiovascular disease (CVD). The harmful mutations of LDLR are the main cause of FH. Especially, there is no effective treatment options for homozygous FH (HoFH) patients. Numerous FH cases have been reported, but most mutations remain unvalidated and lack gene correction studies. The study aims to assess the pathogenicity of a novel mutation, LDLR c.331C>T (p.Gln111Ter), and seek its gene correction strategy. The study systematically evaluated a female HoFH patient and her family. Using CRISPR/Cas9 technology, a Huh7 cell line carrying the point mutation was constructed. The impact of this mutation on LDLR protein expression was confirmed by qPCR, Western blot (WB), and immunofluorescence. A high-fidelity gene correction system targeting the LDLR c.331C>T point mutation was established based on the prime editing (PE) technology. The HoFH patient exhibited a biallelic LDLR mutation comprising an LDLR c.1693_1696 del GGCA inherited from her mather and a de novo LDLR c.331C>T (p.Gln111Ter) mutation. In vitro validation indicated that the mutation impaired normal LDLR protein expression, and the candidate gene editing system achieved approximately 98% correction efficiency. LDLR c.331C>T is a likely pathogenic mutation, which canbe precisely corrected by PE technology. The study expands the spectrum of likely pathogenic mutations in FH and holds promise for personalized, precise gene therapy through customized therapeutic systems, potentially alleviating or curing HoFH-a current challenge in conventional clinical management.
2026-06-09 | Table 1_A de novo LDLR mutation in severe familial hypercholesterolemia: case report, functional characterization, and a personalized gene correction strategy exploration.docx
Background Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by elevated plasma low-density lipoprotein resulting in cardiovascular disease (CVD). The harmful mutations of LDLR are the main cause of FH. Especially, there is no effective treatment options for homozygous FH (HoFH) patients. Numerous FH cases have been reported, but most mutations remain unvalidated and lack gene correction studies. The study aims to assess the pathogenicity of a novel mutation, LDLR c.331C>T (p.Gln111Ter), and seek its gene correction strategy. Methods The study systematically evaluated a female HoFH patient and her family. Using CRISPR/Cas9 technology, a Huh7 cell line carrying the point mutation was constructed. The impact of this mutation on LDLR protein expression was confirmed by qPCR, Western blot (WB), and immunofluorescence. A high-fidelity gene correction system targeting the LDLR c.331C>T point mutation was established based on the prime editing (PE) technology. Results The HoFH patient exhibited a biallelic LDLR mutation comprising an LDLR c.1693_1696 del GGCA inherited from her mather and a de novo LDLR c.331C>T (p.Gln111Ter) mutation. In vitro validation indicated that the mutation impaired normal LDLR protein expression, and the candidate gene editing system achieved approximately 98% correction efficiency. Conclusion LDLR c.331C>T is a likely pathogenic mutation, which canbe precisely corrected by PE technology. The study expands the spectrum of likely pathogenic mutations in FH and holds promise for personalized, precise gene therapy through customized therapeutic systems, potentially alleviating or curing HoFH—a current challenge in conventional clinical management.
2026-04-17 | Severe polyarterial involvement in a 16-year-old with homozygous familial hypercholesterolaemia: a case report.
Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by an elevated plasma concentration of low-density lipoprotein cholesterol (LDL-C) starting at birth and a significantly increased risk of premature atherosclerotic cardiovascular disease. We report the case of a 16-year-old female patient, with no known consanguinity, presented to our cardiology department for anginal chest pain on exertion associated with headaches. She presented with characteristic morphological features of FH. Her lipid profile revealed extremely high LDL-C levels (706 mg/dL) and such extensive arterial and cutaneous involvement. This case underscores the importance of recognizing xanthomas and their association with an increased risk of coronary atherosclerosis.
2026-02-26 | Hepatocyte-Specific Knockout of YAP Protects Against Atherosclerosis via Inhibition of ANGPTL3 in Mice.
Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Hyperlipidemia models were generated in apoE knockout (apoE-/-) mice or mice injected with adeno-associated virus 8-D377Y-mPCSK9, which degrades and deletes LDLR (low-density lipoprotein receptor), by being fed a high-cholesterol diet for 12 weeks. We measured the expression level of hepatic YAP in these apoE-/- mice. Next, we created YAPΔHep (hepatocyte-specific deletion of Yes-associated protein) apoE-/- mice to further determine the role of YAP in hyperlipidemia and atherosclerosis. AML12 (alpha mouse liver 12) cells and mice injected with AAV8-D377-mPCSK9 (adeno-associated virus 8 carrying the D377Y mutant of mouse proprotein convertase subtilisin/kexin type 9) or YAPΔHepapoE-/- mice were used to elucidate its mechanism. Finally, apoE-/- or LDLR knockout (LDLR-/-) mice were used to observe the therapeutic efficacy of adeno-associated virus 8-Alb (albumin)-shYAP (short hairpin RNA targeting for YAP) for hyperlipidemia and atherosclerosis. High-cholesterol diet-fed apoE-/- mice showed increased levels of YAP in the liver. Further investigation indicated that YAPΔHepapoE-/- mice exhibited lighter hyperlipidemia and atherosclerosis than YAPflox/floxapoE-/- mice fed with a high-cholesterol diet. Conversely, hepatocyte-specific overexpression of YAP (5S) deteriorated hyperlipidemia and atherosclerosis in high-cholesterol diet-fed apoE-/- mice. Furthermore, the lipid-lowering effect of YAP deficiency in hepatocytes was independent of LDLR. Hepatocyte-specific overexpression of ANGPTL3 (angiopoietin-like 3) aggravated hyperlipidemia and atherosclerosis in YAPΔHepapoE-/- mice, indicating that ANGPTL3 is responsible for the function of YAP in hyperlipidemia. Mechanistically, YAP upregulated ANGPTL3 via TEAD (TEA domain family member) 4 in hepatocytes independent of LDLR. Notably, adeno-associated virus 8-Alb-shYAP lowered lipid levels in apoE-/- or LDLR-/- mice. Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia.
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2026-07-12 | The Angiopoietin-like Protein (ANGPTL) Axis in Dyslipidemia: Mechanisms, Cardiovascular Risk, and Emerging Therapies.
The angiopoietin-like protein (ANGPTL) 3-4-8 axis has emerged as a central regulator of lipoprotein lipase and lipid metabolism. This review examines the mechanistic basis of ANGPTL pathway modulation and therapeutic implications for cardiovascular risk reduction across diverse phenotypes of dyslipidemia. Genetic studies demonstrate that loss-of-function variants in ANGPTL3 and ANGPTL4 are associated with lower triglycerides and decreased coronary artery disease risk. Pharmacologic inhibition of ANGPTL3 with monoclonal antibodies and RNA-based therapies reduces triglycerides, remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) through mechanisms predominantly independent of the LDL receptor. Clinical trials with ANGPTL3 inhibitors have demonstrated marked LDL-C reductions in patients with homozygous familial hypercholesterolemia (HoFH), as well as broad lipid-lowering effects in patients with mixed dyslipidemia. Emerging strategies targeting the ANGPTL3/8 complex and ANGPTL4 further refine lipid-lowering effects, while early genome-editing data suggest the potential for durable ANGPTL3 suppression. Modulation of the ANGPTL-lipoprotein lipase axis is a novel strategy to address residual atherosclerotic risk beyond traditional LDL receptor-dependent therapies. ANGPTL3 inhibitors have been practice-changing in HoFH, and more broadly, ANGPTL-directed therapies hold promise for patients with mixed dyslipidemia to mitigate cardiovascular risk.
2026-07-02 | Homozygous familial hypercholesterolemia, experience with Evinacumab treatment in two Mexican pediatric patients: case report
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.
2026-06-24 | Management of autosomal recessive hypercholesterolemia in a patient with an LDLRAP1 mutation.
Familial hypercholesterolemia (FH) is characterized by a lifelong elevation of low-density lipoprotein cholesterol (LDL-C), conferring an increased risk of premature atherosclerotic disease and its associated burden of morbidity and mortality. Autosomal recessive hypercholesterolemia (ARH) is a rare form of homozygous FH (HoFH) and is a distinct subset caused by mutations in the low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene. We present a 29-year-old South Asian male who visited the lipid clinic with a markedly elevated, untreated LDL-C level of 557 mg/dL. Clinical and genetic evaluation identified a homozygous pathogenic splice donor variant in the LDLRAP1 (c.344+1G>A), confirming the diagnosis of ARH. On examination, a grade III/VI systolic ejection murmur was appreciated, prompting further investigation that confirmed mild aortic stenosis. Achieving adequate LDL-C control for this patient required stepwise escalation of the lipid-lowering therapy comprising high-intensity statin therapy, proprotein convertase subtilisin/kexin type 9 inhibitor, bempedoic acid, and ultimately evinacumab. This case draws attention to the importance of appropriately diagnosing and treating individuals with ARH and initiating combination lipid-lowering therapy, including specialty medications indicated for this diagnosis, to effectively treat this disorder, as well as the importance of screening for valvular heart disease in this population.
2026-05-15 | EVINACUMAB, A NEW TREATMENT FOR FAMILIAL HYPERCHOLESTEROLAEMIA: MECHANISM OF ACTION, SAFETY AND EFFICACY
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels and a markedly increased risk of premature atherosclerotic cardiovascular disease. The aim of this review was to summarize current knowledge on the pathophysiology, diagnosis, and management of HoFH, with particular emphasis on angiopoietin-like protein 3 (ANGPTL3) inhibition and the clinical role of evinacumab. A comprehensive analysis of published clinical trials, guidelines, and observational studies was conducted to evaluate available diagnostic criteria and therapeutic strategies. Standard lipid-lowering therapies often fail to achieve recommended LDL-C targets in HoFH due to impaired LDL receptor function. Evinacumab, a fully human monoclonal antibody targeting ANGPTL3, has demonstrated substantial LDL-C reductions independent of LDL receptor activity in both adult and pediatric patients. Clinical studies report LDL-C reductions of approximately 45–50%, along with a favorable safety profile. In conclusion, ANGPTL3 inhibition with evinacumab represents a significant advancement in the treatment of HoFH, offering an effective therapeutic option for patients with inadequate response to conventional lipid-lowering therapies.
2026-05-07 | Promise of ANGPTL3 as a therapeutic target for controlling cholesterol levels.
Angiopoietin-like protein 3 (ANGPTL3) has emerged over the past decade as one of the most intriguing therapeutic targets in lipid metabolism. Genetic deficiency of ANGPTL3 in humans produces a striking pan-hypolipidemic phenotype, with reductions in triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), accompanied by protection from atherosclerotic cardiovascular disease (ASCVD). These observations rapidly catalyzed the development of pharmacologic strategies to inhibit ANGPTL3 using monoclonal antibodies (e.g. evinacumab), antisense oligonucleotides (e.g. vupanorsen), small interfering ribonucleic acid (e.g. zodasiran and solbinsiran), and most recently genome-editing approaches (e.g. VERVE-201 and CTX310). However, clinical experience has revealed a more complex and context-dependent biology than initially anticipated. This review examines whether ANGPTL3 should be considered a clinically meaningful cholesterol-lowering target, as exemplified by efficacy of ANGPTL3 inhibition in homozygous familial hypercholesterolemia, or whether its principal therapeutic value lies in modulation of triglyceride-rich lipoproteins and remnant cholesterol, with secondary effects on LDL-C. The degree of hypertriglyceridemia in the patient's baseline lipid profile appears to be an important determinant of drug response. Drawing on genetic, mechanistic, and clinical trial data, the promise and limitations of ANGPTL3 inhibition are considered and its potential place in future lipid-lowering strategies is outlined.
other
2026-06-04 | New and Emerging Therapeutic Targets for ApoB-Containing Particles Lowering.
ApoB is the structural protein of all atherogenic lipoproteins, including VLDLs (very-low-density lipoproteins), IDLs (intermediate-density lipoproteins), LDLs (low-density lipoproteins), chylomicron remnants, as well as Lp(a) (lipoprotein[a]). Because each lipoprotein particle contains a single apoB molecule, plasma apoB concentration reflects the number of circulating atherogenic particles. Genetic, epidemiological, and randomized clinical trial evidence consistently demonstrate that, on a per-particle basis, apoB is a more accurate causal determinant of atherosclerotic cardiovascular disease risk than LDL cholesterol alone. Beyond atherosclerosis, apo B48-containing chylomicrons play a central role in severe hypertriglyceridemia and, importantly, contribute to the risk of triglyceride-mediated acute pancreatitis. Most established therapies that reduce major cardiovascular events, including statins, ezetimibe, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, and bempedoic acid, act primarily by enhancing LDL receptor-mediated clearance of apoB-containing particles. Other currently available therapies reduce LDL cholesterol as well as apoB through LDL receptor-independent mechanisms. Lomitapide, an inhibitor of MTP (microsomal triglyceride transfer protein), and evinacumab, a monoclonal antibody targeting ANGPTL3 (angiopoietin-like protein 3), reduce LDL cholesterol in homozygous familial hypercholesterolemia by decreasing triglyceride-rich apoB-containing lipoproteins upstream of LDL particle formation. Emerging therapeutic strategies targeting the angiopoietin-like protein axis, apo CIII, Lp(a), CETP (cholesteryl ester transfer protein), hepatic lipid flux, and incretin signaling expand the therapeutic landscape for modulating apoB-containing lipoproteins. Gene-targeted approaches, including gene editing, epigenome editing, small interfering RNA, and antisense oligonucleotides, as well as novel oral or injectable agents and combination therapies, further broaden opportunities for durable apoB modulation. Transitioning from an LDL cholesterol-centric to an apoB-centric framework may represent a biologically integrated strategy to reduce both atherosclerotic cardiovascular disease and triglyceride-mediated pancreatitis risk.
2026-02-28 | Variable phenotype associated with compound LDLR gene mutations in familial hypercholesterolemia patients: Case series and clinical implications.
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder with an extremely elevated level of low-density lipoprotein (LDL) cholesterol (LDL-C) and accelerated premature coronary artery disease (PCAD). It is primarily caused by a single pathogenic variant of the LDL receptor (LDLR) gene. This report presents 2 rare and unrelated cases of HoFH with compound LDLR mutations. These 2 individuals presented with atypical clinical features and demonstrated variable degrees of hypercholesterolemia. Case 1 is a 36-year-old Malay woman identified during family cascade screening with a pretreated LDL-C of 8.5 mmol/L and a strong family history of PCAD. Case 2 is a 58-year-old Indian woman discovered to have a pretreated LDL-C of 5.2 mmol/L during routine health screening, without a significant family history of hypercholesterolemia or PCAD. Neither patient demonstrated tendon xanthomas or other lipid stigmata. Both patients underwent lipid profiling and targeted next-generation sequencing of FH-related genes (LDLR, APOB, PCSK9, ABCG5, and ABCG8). Two novel LDLR variants were identified in exon 18: c.2548-1_2548delGAinsTC (pathogenic) and c.2556_2557insTCAGTCTGG (p.Leu853Serfs*12; likely pathogenic) and classified according to American College of Medical Genetics and Genomics guidelines. Case 1 was homozygous for both variants, while Case 2 was homozygous for the splice-site variant and heterozygous for the frameshift variant. Both patients received guideline-directed lipid-lowering therapy and ongoing cardiovascular risk management. Despite biallelic LDLR variants, both patients demonstrated relatively milder hypercholesterolemia and absence of classical HoFH stigmata. The LDLR variants located in exon 18 affecting the cytoplasmic tail domain may be associated with attenuated clinical expression. Recognition of genotype-phenotype variability is crucial for accurate diagnosis, risk stratification, and individualized management of HoFH.
2026-02-14 | A nationwide genetic and phenotypic spectrum of 63 probands of homozygous familial hypercholesterolemia in Taiwan.
The genetic and phenotypic spectrum of homozygous familial hypercholesterolemia (HoFH) in Han Chinese populations remains insufficiently defined. To delineate the nationwide genetic and clinical features of HoFH in Taiwan, including true HoFH, double heterozygous FH (HeFH), and compound HeFH. Patients with clinically diagnosed probable or definite FH enrolled in the Taiwan FH Registry who underwent genetic testing between 2006 and 2025 were analyzed. A comprehensive workflow integrating microarray assay, mass spectrometry, targeted next-generation sequencing, and multiplex ligation-dependent probe amplification was implemented. Variants were classified using American College of Medical Genetics and Genomics guidelines. Of 1479 screened individuals, 63 were genetically confirmed to have HoFH (mean age, 32.8 ± 22.7 years), including 28.6% with atherosclerotic vascular disease. The cohort comprised 14 true HoFH (including homozygous APOB variants), 6 double HeFH, and 43 compound HeFH. The highest documented low-density lipoprotein cholesterol (LDL-C) levels were 357.3 ± 123.5 mg/dL in true HoFH, 347.3 ± 39.2 mg/dL in double HeFH, and 443.5 ± 170.9 mg/dL in compound HeFH. The most frequent genotypes were LDLR [IVS2+4A>T];[IVS2+4A>T] in true HoFH, [APOB p.R3527W];[LDLR IVS2+4A>T] and [APOB p.R3527W];[LDLR p.D90N] in double HeFH, and LDLR [p.D90N];[p.C329Y] in compound HeFH. Patients with double HeFH had lower LDL-C levels and fewer xanthomas than those with LDLR homozygosity or compound mutations, while individuals with homozygous LDLR exon deletions/duplications had the highest LDL-C levels. This nationwide study provides the first comprehensive genetic and clinical characterization of HoFH in Taiwan. Our findings highlight the importance of precise genetic diagnosis and early detection strategies in improving outcomes for this high-risk population.
2025-11-03 | Abstract 4365849: Selective Degradation of Excess Free Cholesterol in the Liver by REP-0003 Regresses Atherosclerotic Plaque in Ldlr -/- Mice: A Novel Approach for HoFH
Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR ) gene, leading to severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. In HoFH patients, statins and PCSK9 inhibitors are ineffective and, while new lipid-lowering therapies including angiopoietin-like 3 inhibitors and lomitapide offer hope, they have not been shown to effectively regress existing plaque, highlighting a critical unmet medical need. The Cholesterol Degrading Platform (CDP) is a fusion protein that degrades excess intracellular free cholesterol into a non-toxic, excretable catabolite to safely regress cholesterol-rich vulnerable plaque. We propose that excess free cholesterol from hypercholesterolemia impairs mechanisms that can otherwise regress atherosclerotic plaque, and that the selective degradation of this free cholesterol in the liver will restore liver health and promote plaque regression throughout the systemic circulation. Methods: Ldlr -/- mice ( n=96 ) were fed a Western diet for 16 weeks and randomized based on body weight and time to exhaustion on an inclined (10%) treadmill. Mice received either intravenous phosphate buffered saline (PBS; equal volume/kg, qw) or REP-0003 (LNP- CDP mRNA ; 0.05–1.50 mg/kg, qw) for 6 weeks followed by another treadmill exhaustion test. At euthanasia, tissues and blood were harvested and assessed for blood chemistries, serum biomarkers, atherosclerotic plaque burden, and histopathology. Results: Compared with PBS, REP-0003 treatment significantly reduced serum alanine transaminase (ALT) levels by 40.5 ± 3.7% ( P<0.01 , indicating improved liver health), reduced serum ApoB levels by 23.9 ± 1.0% ( P<0.01 ) and increased HDL free cholesterol fraction by 61.2 ± 5.8% ( P<0.01 ). Versus controls, (a) aortic root plaque cross-sectional area and aortic tree plaque count/area were significantly reduced by 27.2 ± 4.8% ( P<0.01 ) and 25.8 ± 1.8% ( P<0.05 ), respectively, (b) plaque macrophage infiltration via CD68 staining significantly decreased by 61.5 ± 11.4% ( P<0.01 ), and (c) treadmill runtime significantly increased by 67.2 ± 6.5% ( P<0.01 ). Conclusion: REP-0003 therapy specifically degrades excess free cholesterol in the liver to safely and effectively reduce atherosclerotic plaque burden and enhance exercise tolerance in Ldlr -/- mice, offering a promising first-in-class therapeutic approach for HoFH-associated atherosclerosis.
2024-12-13 | An up-to-date review of emerging biologic therapies for hypercholesterolemia.
Hypercholesterolemia and other lipid disorders are major causes of atherosclerotic cardiovascular disease (ASCVD). Statins have been the mainstay of lipid-lowering therapy for many years, but they may not be adequate to achieve the target low-density lipoprotein (LDL) cholesterol levels and there are other residual lipid risk factors. This article reviews the biologic therapies in development for hypercholesterolemia identified by a PubMed search. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a major focus, but the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3) that were originally developed to reduce the levels of triglyceride-rich lipoproteins are now being explored to reduce cardiovascular events in a wider range of patients. A brief overview of biologic therapies targeting lipoprotein(a) [Lp(a)] is also proved. Inhibition of PCSK9 remains an attractive target. In addition to the currently available monoclonal antibodies (mAbs) and small interfering RNA (siRNA), new mAbs and the adenectin lerodalcibep are promising therapies. The antisense oligonucleotide (ASO) and siRNA inhibitors of apoC3 and ANGPTL3 are effective in severe hypertriglyceridemia and homozygous familial hypercholesterolemia, respectively, and may prove to have wider applications. ASO and siRNA inhibitors of Lp(a) are currently in cardiovascular outcome studies.
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Drug Discovery Landscape
18 orphan drug designations for Homozygous familial hypercholesterolemia, including 7 approved therapies.
18 orphan drug designations for Homozygous familial hypercholesterolemia, including 7 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant adeno-associated virus serotype 8 vector encoding human low-density lipoprotein receptor | gene therapies | FDA | 2025-08-14 | — | NGGT INC. |
mRNA encoding the cholesterol degrading platform (CDP) fusion protein | RNAs | FDA | 2025-05-15 | — | Repair Biotechnologies, Inc. |
bempedoic acid | small molecules | FDA | 2021-04-05 | — | Esperion Therapeutics, Inc. |
Double stranded oligomer RNA interference-based liver targeted therapeutic directed against the ANGPTL3 gene | oligonucleotides | FDA | 2019-07-15 | — | Arrowhead Pharmaceuticals, Inc. |
inclisiran [Leqvio] | RNAs | FDA | 2018-01-22 | 2026-02-12 | Novartis Pharmaceuticals Corporation |
apolipoprotein E mimetic peptide (AEM-28(R)-14) | proteins | FDA | 2017-08-07 | — | LipimetiX Development, LLC |
alirocumab [Praluent] | antibodies | FDA | 2017-06-15 | 2021-04-01 | Regeneron Pharmaceuticals, Inc. |
evinacumab-dgnb [Evkeeza] | antibodies | FDA | 2016-02-08 | 2021-02-11 | Regeneron Pharmaceuticals, Inc. |
2-[4-[[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]acetic acid (1:1) lysine dihydrate | small molecules | FDA | 2015-03-18 | — | Gilead Sciences, Inc. |
rosuvastatin [Crestor] | small molecules | FDA | 2014-02-14 | 2016-05-27 | iPR Pharmaceuticals, Inc. |
gemcabene | small molecules | FDA | 2014-02-06 | — | MetaVia, Inc. |
evolocumab [Repatha] | antibodies | FDA | 2013-09-12 | 2015-08-27 | Amgen Inc. |
apolipoprotein E mimetic peptide | peptides | FDA | 2012-12-03 | — | LipimetiX Development, LLC |
Adeno-Associated Viral Vector Expressing Low-Density Lipoprotein Receptor | gene therapies | FDA | 2012-01-31 | — | ReGenX Biosciences LLC |
lomitapide [Juxtapid] | small molecules | FDA | 2007-10-23 | 2012-12-21 | Chiesi Farmaceutici S.p.A. |
mipomersen [KYNAMRO] | oligonucleotides | FDA | 2006-05-23 | 2013-01-29 | Kastle Therapeutics, LLC |
Implitapide | small molecules | FDA | 2004-08-13 | — | Medical Research Laboratories International |
Sodium dichloroacetate | small molecules | FDA | 1990-06-11 | — | Stacpoole, Peter W. M.D., Ph.D. |
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