Gene Therapy from Naples Offers New Hope for Hereditary Dyslipidemias
Naples, March 24, 2026 – Italian biomedical research has achieved a significant breakthrough in the treatment of familial hypercholesterolemia, a genetic condition characterized by extremely high levels of cholesterol in the blood. The Gene Therapy Laboratory at CEINGE Advanced Biotechnologies in Naples has developed a therapy that directly targets the root cause of the problem, enabling the body to manage cholesterol more effectively.
This innovative approach involves providing the body with a functional version of the LDL receptor, a crucial protein responsible for eliminating ‘bad’ cholesterol. The novelty lies in assigning this function to muscle tissue, which then continuously produces the therapeutic protein. Preclinical tests have shown significant improvements in cholesterol levels and a reduction in arterial lesions, paving the way for more stable and long-lasting therapies.
Familial Hypercholesterolemia: A High-Risk Systemic Condition
Familial hypercholesterolemia is an inherited disorder marked by elevated LDL cholesterol levels from childhood, leading to an accelerated progression of cardiovascular risk and a higher likelihood of acute events at a relatively young age. The condition is primarily linked to mutations in the LDLR gene, which impair the function of the receptor responsible for removing cholesterol from the bloodstream.
Under normal physiological conditions, the LDL receptor allows hepatic and peripheral cells to absorb low-density lipoproteins, maintaining the lipid balance in the plasma. When this function is compromised, the system becomes inefficient, and LDL particles remain in circulation, leading to progressive accumulation, particularly in arterial walls. The resulting atherosclerotic process causes structural changes in blood vessels, including wall thickening, reduced elasticity, and plaque formation, which can obstruct blood flow and cause ischemic events. This necessitates intensive and continuous therapeutic management to reduce cardiovascular risk and maintain lipid levels within preventive limits.
Helper-Dependent Adenoviral Vectors: Structure and Function
The technology developed by CEINGE relies on helper-dependent adenoviral vectors, gene transfer systems designed to deliver genetic material effectively and safely into target cells. These vectors are derived from viruses that have been modified and stripped of their replication-essential sequences, a characteristic that allows their use in therapy by reducing the risks associated with viral activity.
The vector carries a functional copy of the LDLR gene and introduces it into muscle cells via intramuscular injection, initiating the synthesis of the therapeutic protein. This new technology offers high transfer efficiency and good stability of gene expression over time. Another notable feature is the ability of these vectors to carry complex genetic sequences without compromising system safety, making them particularly suitable for developing gene therapies for systemic diseases.
Skeletal Muscle as an Active Biological Platform
The selection of skeletal muscle as the site for therapeutic gene expression is one of the most innovative aspects of this strategy. It leverages the physiological characteristics of muscle, a highly vascularized tissue with significant protein synthesis capacity. Following intramuscular injection, the adenoviral vector introduces the LDLR gene into muscle cells, which then begin to produce the therapeutic protein continuously and stably.
The protein is released into the bloodstream, helping to improve the clearance of LDL lipoproteins, reducing plasma cholesterol concentration, and overall improving lipid metabolism. The muscle thus acts as an active biological platform, capable of sustaining the therapeutic effect over time without the need for repeated administrations. This experimental approach transforms a peripheral tissue into a central element of metabolic regulation, with a systemic impact on the entire body.
Mechanism of Action and Interaction with the Hepatic System
The protein produced by the therapy retains its ability to bind LDL particles and promote their removal from the blood, helping to restore the balance between cholesterol production and clearance. This process integrates with hepatic metabolism, which is the primary system for lipoprotein regulation.
The interaction between the therapeutic protein and the liver enhances the efficiency of LDL uptake, reducing their circulation time in the bloodstream and limiting their deposition in arterial walls. The result is a stabilization of lipid levels and a reduction in the risk of atherosclerosis progression. The mechanism of action is continuous, thanks to constant protein production, and allows for more uniform control of lipid metabolism compared to therapies requiring periodic administrations.
Preclinical Results: Data on LDL and Atherosclerotic Lesions
Studies conducted on murine models with LDL receptor deficiency have shown a significant reduction in LDL cholesterol levels and a decrease in atherosclerotic lesions. These results are maintained over time due to the stability of gene expression. A single intramuscular administration produced a prolonged effect, demonstrating the system’s ability to sustain a lasting therapeutic response.
Histological analyses confirmed the reduction of plaques in the arteries, particularly in the aorta, indicating a direct impact on the pathological process. The data collected so far suggest the possibility of developing a long-term treatment that addresses the cause of the disease.
Safety, Tolerability, and Biological Stability
Evaluations in preclinical models indicate a good safety profile for the treatment, with no significant systemic toxicity observed during the observation period and good tolerability of the viral vector by the treated tissues. The immune response remained within levels compatible with therapeutic use, further strengthening the preclinical profile.
The stability of gene expression is another key strength of the strategy, as it allows for continuous production of the therapeutic protein and more uniform control of lipid levels. Maria Vitale states, “This study demonstrates that a single administration of our muscle-targeted gene therapy can lead to long-term improvement in cholesterol metabolism in models of familial hypercholesterolemia, particularly in patients who do not respond adequately to currently available lipid-lowering therapies.” She adds, “By enabling skeletal muscle to produce a therapeutic protein derived from the LDLR gene, we observed a lasting improvement in lipid levels and a reduction in atherosclerosis for up to three months in preclinical models.” Lucio Pastore emphasizes the need for more effective and durable strategies, noting, “Patients suffering from severe forms of familial hypercholesterolemia often require lifelong continuous treatments and may remain exposed to a high cardiovascular risk.”
Comparison with Current Therapies
Currently available therapies for familial hypercholesterolemia include statins, ezetimibe, PCSK9 inhibitors, and in severe cases, lipoprotein apheresis. These tools reduce cholesterol levels but require continuous management and constant therapeutic adherence. The gene-based approach developed at CEINGE introduces a different mode of intervention, aiming to restore the physiological functioning of the lipid system through a stable modification of the biological system.
Cholesterol and Clinical Guidelines
European guidelines indicate increasingly stringent targets for LDL cholesterol, with values progressively decreasing based on individual cardiovascular risk. They emphasize the importance of continuous monitoring of lipid levels for the prevention of cardiovascular events. Regular monitoring and the adoption of appropriate therapeutic strategies are fundamental tools in disease management.
Future Prospects and Clinical Development
CEINGE’s research paves the way for a possible evolution in the therapy of familial hypercholesterolemia, with the goal of advancing the gene-based approach towards clinical trials and developing a treatment capable of offering lasting benefits with a single administration. The start-up Kimera will support this journey, aiming to translate preclinical results into a therapeutic solution applicable to patients.
What is Cholesterol?
Cholesterol is an essential fatty substance, but its balance is crucial for cardiovascular health. In the blood, it circulates bound to lipoproteins: LDL, often called “bad cholesterol,” promotes plaque formation in arteries, while HDL, considered “good cholesterol,” helps remove excess cholesterol. Alongside these fractions, triglycerides represent another type of fat contributing to the overall lipid profile.
When LDL levels rise, the atherosclerotic process accelerates, increasing the risk of events like heart attack and stroke. The ESC/EAS 2025 guidelines confirm an increasingly decisive orientation towards stringent targets, highlighting how a significant reduction in LDL cholesterol translates into a decrease in cardiovascular events. For the general population, total cholesterol below 190-200 mg/dL is a useful reference, although clinical evaluation primarily focuses on LDL values in relation to individual risk.
Normal Cholesterol Values: Basic References
In adult subjects without specific risk factors, lipid values follow intervals considered physiological. Total cholesterol is ideally below 200 mg/dL, while levels between 200 and 239 mg/dL indicate a borderline situation, and above 240 mg/dL constitutes a high value. LDL cholesterol should preferably remain below 100-130 mg/dL, with optimal levels between 100 and 129 mg/dL in low-risk subjects.
For HDL, values above 40 mg/dL in men and 50 mg/dL in women represent a favorable condition. Finally, triglycerides should remain below 150 mg/dL. These parameters are general references but become more stringent in the presence of risk factors or a family history of cardiovascular diseases.
Cholesterol and Cardiovascular Risk: Personalized Targets
European guidelines distinguish different levels of cardiovascular risk, each associated with specific targets for LDL cholesterol. In low-risk subjects, the reference value is below 116 mg/dL, while in moderate-risk subjects, the target drops below 100 mg/dL.
When the risk becomes high, the LDL value must drop below 70 mg/dL, with a reduction of at least 50% from initial levels. In very high-risk patients, such as those who have already experienced cardiovascular events or have complex pathologies, the target drops further below 55 mg/dL. More recently, the extreme risk category has also been introduced, with even lower targets, down to values below 40 mg/dL. In this context, total cholesterol maintains an indicative role, while clinical management focuses more precisely on LDL control.
Factors Influencing Cholesterol Levels
Cholesterol levels depend on a combination of biological and behavioral factors. Age, sex, and genetics play a decisive role: in women, for example, LDL cholesterol tends to increase after menopause. Lifestyle also has a significant impact. Smoking, physical inactivity, and a diet rich in saturated fats promote increased cholesterol, while regular physical activity and a balanced diet help improve the lipid profile. Conditions like hypothyroidism and metabolic syndrome can further alter these balances, necessitating more frequent monitoring. In subjects with a family history of familial hypercholesterolemia, targets become stricter at a young age.
How to Correctly Read Blood Tests
Cholesterol tests provide essential information for cardiovascular risk assessment but must be interpreted in the overall clinical context. Blood samples are generally taken after fasting to ensure greater accuracy of results. The LDL value is often calculated using the Friedewald formula, although direct measurement is preferred in the presence of high triglycerides. Data interpretation must always be related to the individual risk level, using tools like SCORE2 calculators to estimate ten-year cardiovascular risk. When values exceed recommended limits, the first step involves a comprehensive evaluation that considers lifestyle, family history, and any associated pathologies.
Effective Strategies for Cholesterol Control
Cholesterol control primarily involves lifestyle. A Mediterranean diet, rich in fiber, fruits, vegetables, fish, and extra virgin olive oil, is one of the most effective dietary models for improving the lipid profile. Regular physical activity, with at least 150 minutes per week of moderate aerobic exercise, helps reduce LDL cholesterol and increase HDL. Maintaining body weight and reducing alcohol and sugar consumption complete the picture of preventive strategies. Smoking cessation produces rapid and significant effects on the cardiovascular system, particularly improving HDL cholesterol levels.
Medications and Therapies: When Lifestyle Isn’t Enough
When lifestyle modifications are insufficient to achieve lipid targets, pharmacological therapies come into play. Statins are the reference treatment and allow a significant reduction in LDL cholesterol. Combination with ezetimibe or other drugs can achieve more marked results, especially in high-risk patients. PCSK9 inhibitors offer a further reduction in LDL levels in more complex cases. Recent guidelines encourage an early combined approach in patients with persistently elevated values, aiming to rapidly achieve therapeutic targets. Monitoring after 4-6 weeks from the start of therapy allows for effective treatment adjustment.
Cholesterol Control and Prevention
Cholesterol control is one of the pillars of cardiovascular prevention. Reference values are not fixed but depend on the individual risk profile and the presence of predisposing factors. The ESC/EAS 2025 guidelines confirm the importance of maintaining increasingly lower LDL levels in high-risk patients, with the aim of reducing the incidence of cardiovascular events. An integrated approach combining a healthy lifestyle, regular monitoring, and targeted therapies yields the best long-term results.
Source: https://notizie.tiscali.it/salute/articoli/terapia-genica-colesterolo-napoli/
