Key result
Prime editing corrects ~98% of a pathogenic LDLR mutation in a cellular model, restoring expression.
Why the study?
Homozygous familial hypercholesterolemia lacks effective treatment options, and most reported LDLR mutations remain unvalidated and lack gene correction studies.
Does prime editing correct the LDLR c.331C>T mutation and restore LDLR function in a cellular model of homozygous familial hypercholesterolemia?
Case Report (n=1)
No
Does prime editing correct the LDLR c.331C>T mutation and restore LDLR function in a cellular model of homozygous familial hypercholesterolemia?
The novel LDLR c.331C>T mutation is highly pathogenic in familial hypercholesterolemia, but its functional defects can be efficiently reversed in vitro using prime editing, offering a potential future personalized gene therapy strategy.
Supports preclinical gene editing for this LDLR variant in HoFH; leaves open clinical translation.
Background Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by elevated plasma low-density lipoprotein resulting in cardiovascular disease (CVD). The harmful mutations of LDLR are the main cause of FH. Especially, there is no effective treatment options for homozygous FH (HoFH) patients. Numerous FH cases have been reported, but most mutations remain unvalidated and lack gene correction studies. The study aims to assess the pathogenicity of a novel mutation, LDLR c.331C>T (p.Gln111Ter), and seek its gene correction strategy. Methods The study systematically evaluated a female HoFH patient and her family. Using CRISPR/Cas9 technology, a Huh7 cell line carrying the point mutation was constructed. The impact of this mutation on LDLR protein expression was confirmed by qPCR, Western blot (WB), and immunofluorescence. A high-fidelity gene correction system targeting the LDLR c.331C>T point mutation was established based on the prime editing (PE) technology. Results The HoFH patient exhibited a biallelic LDLR mutation comprising an LDLR c.1693_1696 del GGCA inherited from her mather and a de novo LDLR c.331C>T (p.Gln111Ter) mutation. In vitro validation indicated that the mutation impaired normal LDLR protein expression, and the candidate gene editing system achieved approximately 98% correction efficiency. Conclusion LDLR c.331C>T is a likely pathogenic mutation, which canbe precisely corrected by PE technology. The study expands the spectrum of likely pathogenic mutations in FH and holds promise for personalized, precise gene therapy through customized therapeutic systems, potentially alleviating or curing HoFH—a current challenge in conventional clinical management.
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Zhang et al. (2026) conducted a case report in Homozygous familial hypercholesterolemia (n=1). Prime editing (PE) gene correction vs. Uncorrected mutant cells was evaluated on Gene correction efficiency. A prime editing system achieved approximately 98% correction efficiency of the pathogenic de novo LDLR c.331C>T mutation in a cellular model, restoring LDLR expression.
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