PURPOSE OF REVIEW: Homozygous familial hypercholesterolemia (HoFH) is a rare 
disorder associated with early atherosclerotic disease due to impairment of the 
LDL receptor (LDLR) pathway. Because of their molecular defect, current 
treatment options have limited success in bringing HoFH patient to LDL-C target 
and morbidity and mortality remain high. We review current and upcoming 
therapies directed at HoFH, including gene therapy.
RECENT FINDINGS: Recent real-world studies have confirmed the strength in 
lomitapide as a treatment adjunct to statins and other lipid-lowering therapies 
in HoFH patients. The approval of proprotein convertase subtilisin/kexin type 9 
(PCSK9) inhibitor monoclonal antibodies has also been a welcome addition to the 
treatment armamentarium offering an additional average reduction in LDL-C levels 
of 24% when added to background lipid-lowering therapies in this population. 
Although achieving adequate LDL-C levels in this population is difficult, there 
are several therapies on the horizon that may help more patients reach goal. 
Evinacumab, a monoclonal antibody against ANGPTL3, has been shown to 
substantially reduce LDL-C of an average of 49%, independently of residual LDLR 
activity. RNA interference targeting PCSK9 and ANGPTL3 shows promise in clinical 
trials. Adeno-associated virus-mediated gene transfer and gene editing 
techniques are in early clinical and preclinical development.
SUMMARY: LDL-C lowering in HoFH patients remains very challenging. However, 
novel treatment options are emerging. Upcoming therapies directed at PCSK9 and 
ANPTL3 may offer additional LDL-C reduction, to help patients achieve adequate 
LDL-C levels. Gene therapy and gene editing techniques, if proven effective, may 
offer a unique opportunity to treat patients with a one-time treatment.