About

Marina Cuchel, MD, PhD, is a Research Associate Professor of Medicine in the Department of Medicine at the University of Pennsylvania, specializing in translational medicine and human genetics. She is a member of the Institute for Translational Medicine and Therapeutics (ITMAT) and serves as a physician-scientist on the University of Pennsylvania Institutional Review Board. Dr. Cuchel's research focuses on rare disorders affecting LDL and HDL cholesterol metabolism, with particular emphasis on understanding their causes, developing novel treatments, and improving clinical management. Her active research areas include Homozygous Familial Hypercholesterolemia (HoFH), a rare and severe form of familial hypercholesterolemia, and LCAT deficiency disorders. She has contributed to the development of innovative therapies such as gene therapy, lomitapide, and evinacumab for HoFH. Additionally, her work involves studying familial LCAT deficiency and fish-eye disease, which are associated with very low HDL levels and other complications. Dr. Cuchel leads clinical research programs and registries related to these conditions, aiming to gather data and advance treatment options. Her extensive publication record reflects her expertise and ongoing contributions to lipid disorder research.

Research topics

• Medicine
• Internal medicine
• Endocrinology
• Chemistry
• Biology

Selected publications

• Traditional cardiovascular risk factors and their association with atherosclerotic cardiovascular disease in homozygous familial hypercholesterolemia: A cross-sectional analysis from the HICC registry

  Atherosclerosis · 2026-03-24 · 1 citations

  articleOpen access

  BACKGROUND AND AIMS: As survival improves in patients with homozygous familial hypercholesterolemia (HoFH), exposure to traditional cardiovascular risk factors may increasingly influence outcomes. This study aimed to determine the prevalence of traditional coronary artery disease (CAD) risk factors-hypertension, diabetes, smoking, and obesity-and their associations with CAD in HoFH. METHODS: We performed a cross-sectional analysis of patients enrolled in the HoFH International Clinical Collaborators (HICC) registry (NCT04815005) between February 2016 and December 2024. Logistic regression was used to estimate the association between risk factors and CAD in risk factor propensity score-matched subgroups. Analyses were stratified by sex, on-treatment LDL-C tertiles, and country-income status. RESULTS: Among 912 patients with HoFH (53.3% female; median age 33.0 years), the prevalence of hypertension was 16.5%, diabetes 3.8%, smoking 8.2%, overweight 25.4%, and obesity 17.6%. Cardiovascular risk factors were more frequent in older patients (e.g., hypertension: 25.7% ≥ 30 years vs. 4.3% < 30 years; p < 0.001), in those from high-income countries (17.8% vs. 14.9%; p = 0.011), and in those achieving lower LDL-C levels (24.1% in the lowest vs. 14.6% in the highest LDL-C tertile; p = 0.004). After propensity score matching, hypertension was significantly associated with CAD (OR 1.85; 95%CI 1.11-3.08, p = 0.02), while diabetes, smoking, and obesity were not associated. CONCLUSIONS: Despite the dominant role of cumulative LDL-C burden in the development of CAD, our findings indicate an association between hypertension and CAD in HoFH. Although causal inference is limited by the cross-sectional design, these results highlight the importance of proactive identification and management of hypertension in HoFH alongside intensive lipid-lowering therapy.

  PublisherDOI

• Abstract We0092: A Loss-of-Function Missense Variant in ANGPTL3 Exerts Protective Effects Against Kidney Disease Risk

  JVS Vascular Science · 2026-01-01

  articleOpen accessSenior author
  PublisherDOI

• Update on familial hypercholesterolemia: An expert clinical consensus from the National Lipid Association

  Journal of clinical lipidology · 2026-01-29 · 3 citations

  article
  PublisherDOI

• Liver transplantation in severe homozygous familial hypercholesterolaemia: a scoping review

  Atherosclerosis · 2026-04-09 · 2 citations

  articleOpen access

  BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  PublisherDOI

• Homozygous Familial Hypercholesterolemia Is a Life-Limiting Condition

  Journal of the American College of Cardiology · 2025-05-01 · 10 citations

  articleOpen access
  PublisherOA PDFDOI

• Abstract We0092: A Loss-of-Function Missense Variant in <i>ANGPTL3</i> Exerts Protective Effects Against Kidney Disease Risk

  Arteriosclerosis Thrombosis and Vascular Biology · 2025-04-01

  articleSenior author

  Introduction: Angiopoietin-like protein 3 (ANGPTL3) is a liver-secreted protein with well-characterized effects on inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL) activity, thus increasing levels of circulating triglycerides, LDL-C, and HDL-C. However, the effects of loss-of-function variants in this gene on kidney disease risk are not well understood. In this study, we identified a missense variant M259T in ANGPTL3 and characterized its protective role against kidney disease. The variant is most strongly represented in the African population with a gnomAD minor allele frequency (MAF) of 0.05 compared to a European population MAF of 7.30E-05. Methods: We leveraged the Penn Medicine Biobank as our study cohort both for its extensive phenotyping from the electronic health records and its population diversity in that over 25% of individuals with genetic sequencing data are of African (AFR) ancestry ( n = 11,198). All variant-phenotype associations were performed using a generalized linear mixed model controlling for age, sex, ancestry-specific genetic principal components, and genetic relatedness. Quantitative traits were all rank-based inverse normal transformed. Results: In the AFR population, the M259T variant was found to be associated with decreased triglycerides (beta = -0.09, P = 5.09E-03), consistent with loss-of-function of ANGPTL3. This association was replicated (beta = -0.08, P = 1.24E-10) in the AFR population ( n = 121,790) from the Million Veteran Program (MVP). Interestingly, this variant was also significantly associated with increased eGFR (beta = 0.10, P = 2.82E-04) and decreased creatinine (beta = -0.10, P = 5.59E-04) in PMBB. The association with decreased creatinine almost reached significance in MVP (beta = -0.01, P = 0.06). Further stratifying the PMBB cohort by their APOL1 G1/G2 risk carrier status, we observed strong persistent protective effects including increased eGFR (beta = 0.09, P = 1.49E-03) and decreased creatinine (beta = -0.09, P = 3.67E-03) in low-risk individuals who carry either 0 or 1 copy of G1/G2. The protective signals were slightly weaker in high-risk individuals who carry 2 copies of G1/G2, likely due to the large risk-conferring effects of the APOL1 risk alleles. Conclusion: Our results suggest that loss-of-function in ANGPTL3 may play an independent protective role in kidney disease risk, but additional analyses are required to confirm and uncover the biological mechanisms involved.

  PublisherDOI

• A loss-of-function missense variant in ANGPTL3 exerts protective effects against kidney disease risk

  Atherosclerosis · 2025-07-18

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Impact of Evinacumab on coronary plaques in patients with Homozygous Familial Hypercholesterolemia: Protocol of the "EVOLVE-HoFH" study (EValuation of atherOma pLaque Volume after Evinacumab in HOmozygous Familial Hypercholesterolemia)

  European Atherosclerosis Journal · 2025-12-31

  articleOpen access

  Background: Homozygous Familial Hypercholesterolemia (HoFH) is a rare and severe genetic disorder characterized by markedly elevated low-density lipoprotein-cholesterol (LDL-C) levels from birth onwards, leading to accelerated and premature atherosclerotic cardiovascular disease (ASCVD). Evinacumab, a monoclonal antibody targeting angiopoietin-like protein 3 (ANGPTL3), has been shown to effectively reduce LDL-C in this population. However, its direct impact on coronary atherosclerotic plaque burden remains to be established. Given the rarity of the condition, randomized placebo-controlled clinical trials on major adverse cardiovascular events (MACE) are unfeasible. Aim and Methods: This document describes the methodology of the EVOLVE-HoFH study, a real-world, observational, multicenter, international study (prospective and retrospective) designed to assess whether intensification of lipid-lowering therapy (LLT) with Evinacumab leads to regression or stabilization of the coronary atherosclerotic plaque burden as well as altered composition in patients with HoFH. The study will use Coronary Computed Tomography Angiography (CCTA), a validated surrogate risk marker, to compare changes in plaque volume in a group of patients initiating treatment with Evinacumab ("intensified treatment group") with a "conventional treatment comparator group." The primary endpoint is the difference in change in percent non-calcified plaque volume (%NCPV), a key indicator of plaque instability, between baseline and 18-24 months follow-up. Conclusion: This pragmatic methodological approach is designed to overcome the barriers of research in rare diseases, allowing for the evaluation of a clinically relevant and mechanistically informative surrogate efficacy endpoint. The results will provide the first evidence of the beneficial impact of Evinacumab on coronary atherosclerosis, filling an important knowledge gap.

  PublisherOA PDFDOI

• Long-term experience with lomitapide treatment in patients with homozygous familial hypercholesterolemia: Over 10 years of efficacy and safety data

  Journal of clinical lipidology · 2025-03-01 · 10 citations

  reviewOpen access

  BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by loss of low-density lipoprotein receptor (LDLR) function, an extreme elevation of circulating low-density lipoprotein cholesterol (LDL-C) from birth and substantially reduced life expectancy, if untreated. Patients with HoFH are frequently diagnosed late and have a markedly elevated risk of premature atherosclerotic cardiovascular disease (ASCVD). SOURCES OF MATERIAL: The current European Atherosclerosis Society consensus statement on the treatment of HoFH recommends an LDL-C goal of <55 mg/dL for adults with ASCVD or major ASCVD risk factors, <70 mg/dL for adults without ASCVD risk factors, and <115 mg/dL for pediatric patients without ASCVD. However, achieving these targets is challenging, necessitating treatment with multiple lipid-lowering therapies in combination, including statins, ezetimibe, and other treatments such as lipoprotein apheresis, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), lomitapide, and evinacumab. ABSTRACT OF FINDINGS: Lomitapide is a small molecule inhibitor of microsomal triglyceride transfer protein. As lomitapide reduces the production of apolipoprotein B-containing lipoproteins, its mechanism of action is independent of LDLR. The present review summarizes the available evidence regarding the use of lomitapide for the treatment of patients with HoFH. CONCLUSIONS: Over the last decade, numerous clinical trials, real-world evidence studies, and case studies/series have investigated the LDL-C-lowering efficacy/effectiveness and safety of lomitapide. Lomitapide is an effective treatment option for lowering LDL-C in patients with HoFH who are refractory to LDLR-dependent therapies, such as statins, ezetimibe, and PCSK9i.

  PublisherDOI

• LDL-C–Lowering Therapies for Adults and Children With Homozygous Familial Hypercholesterolemia: Challenges and Successes

  Circulation · 2024-01-29 · 7 citations

  editorialSenior author
  PublisherDOI

Recent grants

• NIH Grant P01HL059407

  NIH · $37.7M · 2021

• NIH Grant R01FD003098

  NIH · $1.0M · 2012

• NIH Grant K23HL077146

  NIH · $662k · 2010

Frequent coauthors

• Daniel J. Rader

  University of Pennsylvania

  144 shared

• Robert A. Hegele

  Western University

  44 shared

• Frederick J. Raal

  35 shared

• Maurizio Averna

  Instituto Biofisika

  34 shared

• G. Kees Hovingh

  33 shared

• John S. Millar

  Durham University

  33 shared

• Alberico L. Catapano

  31 shared

• M. John Chapman

  Sorbonne Université

  31 shared

Labs

• Marina Cuchel LabPI

Education

• Master of Science in Translational Research

  University of Pennsylvania

  2008

• PhD

  Università degli Studi di Milano Facoltà di Medicina e Chirurgia

  1998

• MD

  Università degli Studi di Milano Facoltà di Medicina e Chirurgia

  1987