CorrectSequence Therapeutics Co., Ltd. (Correctseq) has announced that the first patient in its Investigator-Initiated Trial (IIT) of the base-editing therapy CS-121 targeting APOC3 for chylomicronemia/hypertriglyceridemia has successfully completed dosing and been discharged from the hospital.
The patient, diagnosed with chylomicronemia, had a long history of fasting triglyceride (TG) levels exceeding 12.5 mmol/L and recurrent acute pancreatitis. In the dose-escalation IIT for CS-121, his fasting TG level dropped significantly within three days after a single low-dose administration, with no adverse events.
This is the world’s first successful clinical treatment of hyperlipidemia with the gene-editing therapy targeting APOC3.
Chylomicronemia is a metabolic disorder characterized by abnormally elevated chylomicrons in the blood, associated with lipid metabolism dysfunction, leading to extremely high fasting TG levels and potentially life-threatening complications such as acute pancreatitis. It is the most severe subtype of severe hypertriglyceridemia (sHTG), including familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS). FCS is a rare autosomal recessive disorder caused by biallelic mutations in the lipoprotein lipase (LPL) gene or other key regulatory genes, with fasting TG ≥10 mmol/L (885 mg/dL) and a global prevalence of 1 in 100,000–1,000,000. MCS results from a complex interaction of genetic, lifestyle, or metabolic disorders with a prevalence as high as 1 in 600 worldwide.
Current treatments for chylomicronemia primarily aim to control fasting TG levels below the acute pancreatitis risk threshold (<5.7 mmol/L or 500 mg/dL), but available triglyceride-lowering medications are often insufficient, and very-low-fat diets are hard to maintain in a long-term manner.
Scientific studies have shown that the APOC3 protein, produced in the liver, plays a central role in TG regulation. Large-scale population analyses have shown that individuals carrying natural APOC3 loss-of-function mutations have significantly lower TG levels without adverse effects. With advances in gene-editing technologies, it is now possible to therapeutically modulate APOC3 expression at the genetic level to lower TG levels — offering a potential curative strategy for chylomicronemia and hypertriglyceridemia.
CS-121, Correctseq’s first in vivo gene-editing therapy for chylomicronemia and hypertriglyceridemia, is based on the transformer base editor (tBE) — a precise base-editing system independently developed by Correctseq’s scientific co-founders. Administered via intravenous injection, tBE is delivered via lipid nanoparticles (LNPs) to the liver and precisely edits the target APOC3 gene. It mimics beneficial natural APOC3 loss-of-function variants to downregulate APOC3 expression and effectively lower plasma TG levels. By addressing the disease at the genetic level, this therapy aims to achieve “one-time treatment, lifelong efficacy.”
CS-121 utilising the next-generation tBE technology, which enables precise single-base correction without DNA double-strand breaks, offering superior safety over the gene-editing therapies based on CRISPR. tBE avoids potential safety risks such as p53 activation, chromosomal damage, off-target effects, and liver toxicity caused by DNA double-strand breaks. Preclinical animal studies showed excellent safety and long-term efficacy, with no off-target editing detected in various organs including liver, lungs, muscle, spleen, ovaries, heart, and kidneys.
The first patient, a 63-year-old male, received a single low-dose intravenous administration. His fasting TG levels dropped significantly within three days after the treatment, and he was discharged three days post-treatment with no treatment-related adverse events to date.
The principal investigators of the CS-121 IIT are Professor Huan Zhou and Doctor Zhili Wu from the First
Correctseq, an innovative biotechnology company at the IND clinical stage, previously developed CS-101, an ex vivo gene-editing therapy that has successfully treated dozens of patients with β-thalassemia and sickle cell disease. The company is advancing the first in vivo gene-editing therapy CS-121 toward IND clinical trials and commercialization, aiming to offer “one-time treatment, lifelong efficacy” treatment for patients with chylomicronemia, hypertriglyceridemia, and other metabolic disorders.
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