Definition of hypercholesterolemia
Hypercholesterolemia refers to elevated levels of cholesterol in the blood[1]. Cholesterol is one of the three major lipid classes produced by all animal cells and used in the formation of cell membranes. As cholesterol is not soluble in water, it is transported in the bloodstream by protein particles (lipoproteins). Lipoproteins are classified by density: very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL)[2]. All lipoproteins contain cholesterol, but levels of non-HDL cholesterol, especially LDL cholesterol, when elevated over an extended period, can lead to atherosclerosis and trigger coronary heart disease[3, 4]. Conversely, higher levels of high-density lipoprotein cholesterol have a protective effect[5]. Due to irregular dietary habits, disrupted sleep patterns, and increased work-related stress in today's society, the number of people with hypercholesterolemia is on the rise, contributing to the prevalence of cardiovascular diseases.
Challenges in the treatment of hypercholesterolemia
Cardiovascular disease (CVD) is a leading global cause of death, claiming an estimated 17.9 million lives each year. According to surveys, the prevalence of high cholesterol in the United States slightly exceeds 13%. Elevated cholesterol levels are a significant factor in the occurrence of cardiovascular diseases. Given the current considerations, we feel it is imperative to take action to improve the current situation. Through a literature review, we have found that statin medications are the standard treatment for cardiovascular risk. They reduce LDL-C levels or decrease cardiovascular risk by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and have been considered a first-line treatment for over two decades[8]. Statin medications do not have a significant effect on reducing lipoprotein(a). Additionally, niacin, ezetimibe, and bile acid sequestrants are used to lower LDL-C levels. However, 25% of patients receiving statin treatment, especially those with familial hypercholesterolemia, still cannot achieve normal LDL-C levels even at the highest doses. Furthermore, some patients exhibit statin intolerance symptoms, including muscle symptoms, new or worsening diabetes, hemorrhagic stroke, headache, sleep disturbances, rashes, and arthritis[9-11]. Low treatment adherence is also a challenge in the treatment of hypercholesterolemia, with an estimated 50% of patients not taking the required medication correctly. In an observational study conducted in Croatia, only 35% of patients achieved over 70% of the prescribed statin medication dose, with just half (51%) fully adhering to the treatment[12]. Therefore, there is an urgent need to develop a more compliant and efficacious treatment approach, which is also a focal area of our team's efforts.
Synthetic biology is a potential method for treating hypercholesterolemia
The benefits of microbes for overall gut health and immunity have been widely recognized; multiple studies have shown that microbes can alleviate lactose intolerance, have a positive impact on the host's gut microbiota, reduce inflammation or allergic reactions, possess anti-colorectal cancer effects, anti-hypertensive effects[13-15], and reduce clinical symptoms of atopic dermatitis, Crohn's disease, diarrhea, constipation, candidiasis, and urinary tract infections[16-18]. Recently, the cholesterol-lowering effects of microbes have also been researched[19-21]. Numerous animal studies using various strains have demonstrated this effect[22-26]. In recent years, synthetic biology has gained increasing attention in harnessing modified microbes to perform specific functions, which may be a promising direction for treating hypercholesterolemia in the future.
Our Solution
Existing research indicates that the gut microbiota primarily indirectly regulates cholesterol levels through IsmA, BSH, and BCoAT. Furthermore, we have identified an oleic acid inducer, fadR-PfadB, as a unique promoter. In the absence of oleic acid, fadR binds to a 17-bp operator sequence, fadO, on PfadB, repressing the expression of the target genes. When oleic acid is present, the oleoyl coenzyme A produced from it releases fadR, allowing PfadB to initiate normally. By combining IsmA, BSH, and BCoAT genes with the oleic acid inducer and constructing plasmids for bacterial transformation, we have developed a strain of Escherichia coli that can automatically degrade cholesterol in the presence of oleic acid. Additionally, in consideration of human safety, we have collaborated with Beijing University of Chemical Technology to develop a 'suicide switch.' These engineered bacteria show promising potential for treating high cholesterol.
Characteristics and Advantages
The challenges of treating high cholesterol levels have been extensively discussed above. Patient non-compliance is one of the contributing factors to the suboptimal effectiveness of traditional methods. We aim to address this issue by utilizing synthetic biology approaches, which may improve patient compliance. Additionally, traditional statin-like drugs are small-molecule agents, representing a localized molecular-based therapeutic approach. However, the human body functions as an ecosystem, and focusing solely on the local aspect while disregarding the whole can lead to suboptimal therapeutic outcomes. By employing the gut microbiota to treat high cholesterol levels, we consider the entire human ecological system, potentially compensating for the limitations of small-molecule drugs.
Furthermore, it is well-known that pharmaceuticals often exhibit numerous side effects and can lead to drug resistance. Our research begins at the point of cholesterol absorption, which can reduce the trauma to the human body and minimize the development of drug resistance.
References
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