FAMILIAL HYPERCHOLESTEROLEMIA (FH): TREATMENT AND POTENTIAL CURE?
What is Familial Hypercholesterolemia or FH?
FH is an autosomal dominant inherited genetic condition that involves approximately 30 million patients across the world. It is underdiagnosed with only 15% of Americans with FH having received the diagnosis. FH is caused by an abnormal variant of one or more of the 3 main cholesterol genes: 1) >90% involve the LDL receptor, 2) >5% involve the ApoB receptor and 3) <1% involve the PCSK9 receptor.
Heterozygous FH (heFH) is the most common and involves only 1 allele. It is present in 1 in 200-300 adults.
Homozygous FH (hoFH) when the 2 alleles are affected and are present in 1 in 160,000-300,000 adults
What is the problem with FH?
FH is characterized by lifelong exposure to very high levels of LDL cholesterol resulting in an increased risk of premature ASCVD and death. Left untreated, heart disease and stroke are 10-20 fold increased compared to the general population and are manifested in women at the age of 45 in HeFH and in men, at 35, or even as children in HoFH.
HeFH can be diagnosed when LDL is >160 mg/dL in children or when LDL is >190 mg/dL in adults in combination with premature ASCVD or similar LDL in a first-degree relative.
HoFH can be diagnosed when the LDL is >400 mg/dL with parents diagnosed with FH, positive genetic testing or aortic valve disease, or clinical findings of xanthomas or corneal arcus at a young age. An LDL that is extremely elevated at >560 mg/dL confers the diagnosis of hoFH. Genetic testing could be pursued to confirm the diagnosis.
What are the treatments available for FH patients?
Statins constitute the first-line treatment for patients with FH. High-intensity statins, such as atorvastatin or rosuvastatin, can provide a modest reduction in LDL cholesterol (10-25%). The addition of ezetimibe, can reduce the absorption of cholesterol at the level of the small intestine and can add an additional 10-15% reduction in LDL when combined with a healthy lifestyle. Bempedoic acid can also be used to lower the LDL in some patients.
Monoclonal antibodies to PCSK9 have produced a dramatic reduction of cholesterol in patients with a functional LDL receptor. This is not always the case in patients with hoFH where evolocumab reduces the LDL by an average of 20-30% and alirocumab by 36% when combined with statin therapy.
Inclisiran is a small interfering RNA molecule that works at the level of the liver cell. It is currently being studied as part of ORION-5 in patients with HoFH in the background of standard lipid-lowering therapies.
Lomitapide is an oral microsomal transport protein inhibitor involved in the production of VLDL. When combined with standard therapy, it has produced a 50% reduction in LDL cholesterol in patients with HoFH. Limiting side effects on the GI tract and toxicity to the liver have been noted, however.
Often, lipoprotein apheresis or liver transplant are needed in patients with HoFH.
Novel target therapies for FH: Angiopoietin-like 3 (ANGPTL3).
ANGPTL3 is a protein that inhibits the lipoprotein lipase and can reduce lipid levels independently of the LDL receptor. Evinacumab is an antibody that inhibits ANGPTL3 and was approved by the FDA to reduce cholesterol in patients with HoFH. When added to standard therapies, monthly Evinacumab reduced the LDL by 47% compared to baseline. New antisense and small interfering RNA to the ANGPTL3 protein are being studied.
Gene therapy: a potential cure for FH?
Genetic studies have shown that certain individuals are born with gene variants that have natural disease resistance to heart attack and stroke. Some people are born with a variant of the PCSK9 gene, have extremely low LDL, and are healthy and protected against heart attacks. Could gene therapy be used to mimic the protective effect of naturally occurring protective mutations?
ANGPTL3 is also an ideal target for gene therapy. Patients born with a loss of function mutation of the ANGPTL3 gene are protected against coronary artery disease. ANGPTL3 is expressed primarily in the liver which is easily accessible to different delivery approaches. The inhibition of ANGPTL3 requires only the introduction of inactivating mutations.
The main benefit of in-vivo gene editing is that it could yield a one-shot, long-term therapy that could permanently modify the gene and if performed early, reduce the lifelong exposure to very high LDL and the risk of ASCVD as well as remove the need for repeated administration of medications.
The downside is the potential of off-target mutation or unanticipated mutation that could cause cancer or promote a different disease. There are also unintended on-target mutations that could cause irreversible genetic changes with potentially serious adverse effects. What are the repercussions of genetic edits becoming inheritable? Obviously, the best candidate for these new gene editing therapies are patients with hoFH because of the limited response to current therapies. Much more research is needed before these new treatments can be integrated into clinical practice.
This article was written in collaboration with Dr. Pradeep Natarajan, Director of Preventive Cardiology, Massachusets General Hospital, Paul and Phyllis Fireman Endowed Chair in Vascular Medicine, Associate Professor of Medicine, Harvard Medical School.