Cellectis Unveils In Vivo Gene-Editing Plans for Severe Lipid Disorders

Key Points

• Cellectis is advancing two one-time intravenous in vivo gene-editing candidates for severe lipid disorders, using mRNA delivered in lipid nanoparticles to target the liver.
• HEAL-101 targets APOC3 for severe hypertriglyceridemia, while HEAL-201 targets PCSK9 through epigenetic silencing for severe hypercholesterolemia; preclinical studies showed substantial reductions in triglycerides, PCSK9 and related proteins.
• The company plans investigator-initiated trials in China beginning with HEAL-101 in the first quarter of 2027 and HEAL-201 in the second half of 2027, with initial data expected later in 2027 and in the first half of 2028, respectively.

Cellectis NASDAQ: CLLS outlined plans to advance two preclinical in vivo gene-editing candidates for severe forms of dyslipidemia, targeting hypertriglyceridemia and hypercholesterolemia through one-time intravenous treatments.

Chief Executive Officer André Choulika said the company is building on its history in gene editing and shifting its focus toward in vivo approaches, in which a gene editor is delivered directly into the body. Unlike ex vivo gene editing, which involves collecting, modifying and reinfusing cells, in vivo editing uses an injection intended to reach a target tissue and modify gene activity.

The company’s two lead programs use messenger RNA packaged in lipid nanoparticles, or LNPs, to deliver gene-editing tools to the liver. Choulika compared the delivery concept to mRNA-LNP technology used in COVID-19 vaccines, while emphasizing that Cellectis’ products encode gene editors rather than vaccine antigens.

Programs Target APOC3 and PCSK9

HEAL-101 is being developed for severe hypertriglyceridemia and targets APOC3, a gene associated with triglyceride levels. Chief Medical Officer Adrian Kilcoyne said patients with severe hypertriglyceridemia face elevated risks of acute and recurrent pancreatitis, with limited treatment options available.

Cellectis intends to focus on patients with triglyceride levels above 880 milligrams per deciliter, as well as patients above 500 milligrams per deciliter who have experienced prior pancreatitis. Kilcoyne estimated that 1 million to 2 million patients across the U.S. and European Union could fall within those categories.

HEAL-101 uses a TALE base editor designed to convert a cytosine to a thymine within exon 4 of the APOC3 gene. According to Choulika, the edit introduces a stop codon intended to prevent expression of the APOC3 protein without making a DNA break.

In preclinical studies described during the presentation, Cellectis said HEAL-101 modified the intended site at rates approaching 80% and did not show detected off-target edits in the testing presented. In humanized-liver mouse models and transgenic mice expressing human APOC3, the company reported reductions in APOC3 expression and triglyceride levels, including a triglyceride reduction of up to 76% in one model.

The second candidate, HEAL-201, is being developed for severe hypercholesterolemia and targets PCSK9, a well-established target for reducing LDL cholesterol. Kilcoyne said the company sees an opportunity among younger, high-risk patients with genetic disease, premature cardiovascular disease or persistently elevated LDL-C despite maximal therapy. He similarly estimated a target patient population of 1 million to 2 million people across the U.S. and EU.

Epigenetic Approach for PCSK9

Rather than altering the DNA sequence, HEAL-201 is designed to epigenetically silence PCSK9. Choulika said the program uses two TALE binders intended to modify chromatin around the PCSK9 gene, turning off transcription without changing the underlying DNA sequence.

In the preclinical data presented, Cellectis said PCSK9 protein expression was rapidly reduced and that transcriptome analysis showed PCSK9 as the only gene with meaningful downregulation. The company also reported a rapid and durable reduction of PCSK9 in mice with humanized livers.

Choulika said the potential durability of the approach could depend on factors including the rate at which affected cells reproduce and the persistence of the epigenetic modification.

Clinical Timeline and Development Strategy

For both programs, Cellectis plans to initially generate first-in-human data through investigator-initiated trials in China, followed by global Phase Ib/II studies supported by parallel investigational new drug and clinical trial application activities.

• HEAL-101: Cellectis expects to begin an investigator-initiated trial in China in the first quarter of 2027, with initial data anticipated in the second half of 2027.
• HEAL-201: The company expects to begin its China-based investigator-initiated trial in the second half of 2027, with initial data expected in the first half of 2028.

Kilcoyne said the HEAL-101 trial will assess safety, tolerability and efficacy. He noted that triglyceride levels are validated endpoints and said the pancreatitis-focused indication does not require a cardiovascular outcomes trial, according to the company’s development view. For HEAL-201, he said LDL-C is an accepted surrogate marker for approval by the FDA and European Medicines Agency.

During the question-and-answer session, Kilcoyne said market research indicated clinicians could view a durable gene-editing treatment as a potential option for patients who otherwise require lifelong redosing with existing APOC3-directed therapies. Choulika characterized in vivo gene editing as “gene surgery,” contrasting a one-time intervention with chronic drug treatment.

Choulika also said Cellectis’ partnerships with AstraZeneca, Servier, Allogene and Iovance continue unchanged. The company is seeking partnerships for its internal cell-therapy programs, lasme-cel and eti-cel, as it directs organizational priorities toward HEAL-101 and HEAL-201. He said Cellectis’ cash runway extends into the second half of 2028.

About Cellectis (NASDAQ:CLLS)

Cellectis SA NASDAQ: CLLS is a clinical-stage biotechnology company focused on developing gene-edited, allogeneic T-cell therapies for cancer. The company uses its gene-editing technologies, including TALEN-based technology, to modify immune cells so they can be manufactured in advance and potentially administered to multiple patients rather than produced individually.

Cellectis' product candidates are designed primarily as chimeric antigen receptor T-cell (CAR-T) therapies for hematologic malignancies and other serious diseases.

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