The Latest Updates From the Gene-Editing Clinical Trials (February 2025)

YolTech reports first positive clinical data for gene-editing therapy in primary hyperoxaluria type 1

Shanghai-headquartered YolTech Therapeutics reported yesterday positive results from the ongoing investigator-initiated trial of YOLT-203 in patients with primary hyperoxaluria type 1 (PH1).

According to the company’s press release, the clinical data demonstrates excellent safety and pharmacodynamic profiles and the potential of YOLT-203 to effectively normalise urinary oxalate levels in PH1 patients. The first two patients were dosed with YOLT-203 in August 2024 and as of January 2025, seven participants had been enroled. In patients that received the high dose of YOLT-203 (0.45 mg/kg), an almost 70% reduction of 24-hour urinary oxalate levels was observed and sustained through the 16-week primary observation period. YOLT-203 was well tolerated at all dose levels. The company reports no serious adverse events, treatment discontinuations or patient withdrawals.

With these data, YOLT-203 is the first in vivo gene-editing therapy to show positive clinical data for PH1. YOLT-203 received Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA in September 2024.

YOLT-203 targets the HAO1 gene for permanent reduction of liver oxalate levels

PH1 belongs to a family of inherited metabolic disorders and arises through mutations in the AGXT gene, which results in deficiency or dysfunction of the enzyme alanine-glyoxylate aminotransferase. This leads to a harmful accumulation of oxalate in the kidney and other organs. PH1 typically debuts in childhood, and most patients experience kidney failure and require intensive haemodialysis while waiting for dual liver/kidney transplantation.

YOLT-203 is designed to permanently reduce the harmful oxalate levels in the blood by deactivating glycolate oxidase (GO), an enzyme encoded by the HAO1 gene and which plays a key role in oxalate production. By targeting HAO1 instead of AGXT, YOLT-203 has the potential to treat more patients than targeting AGXT, since PH1 can arise through many different mutations in AGXT.

YOLT-203 is developed using YolTech's proprietary YolCas12™ system and consists of the YolCas12 nuclease and target-specific guide RNA. This cargo is delivered intravenously via lipid nanoparticles (LNPs) that traffic to the liver, where it targets HAO1 in liver cells.

The early Phase 1 trial, which is sponsored by RenJi Hospital (Shanghai), aims to evaluate the safety and tolerability of YOLT-203 in Chinese individuals with PH1, and to preliminarily assess the impact of a single dose of YOLT-203 on plasma oxalate levels. In pre-clinical studies published in October 2024, a single in vivo administration of YOLT-203 alleviated PH1 symptoms safely in mice that express human Hao1 (1).

Earlier this month, the FDA granted Orphan Drug and Rare Pediatric Disease designations to Arbor Biotechnologies' ABO-101, a one-time in vivo CRISPR-Cas12i2 therapeutic candidate for PH1 that is also delivered by LNPs to target HAO1. The Phase 1/2 redePHine trial of ABO-101, which is anticipated to begin in the first half of 2025, will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ABO-101 in adult and paediatric PH1 patients. You can read more about ABO-101 here.

Precision BioSciences reports positive initial data for PBGENE-HBV in chronic hepatitis B patients

Durham-based Precision BioSciences announced yesterday positive initial safety and efficacy data from the first cohort of the ELIMINATE-B clinical trial evaluating PBGENE-HBV for chronic Hepatitis B virus (HBV) infection.

According to the company's press release, PBGENE-HBV was safe and well tolerated in all three participants after the first administration at the lowest dose level (0.2 mg/kg). Two of the three participants demonstrated substantial reductions in hepatitis B surface antigen (HBsAg) following this initial administration, suggesting anti-viral activity even at the lowest dose tested.

The ELIMINATE-B protocol is designed for three dose administrations at each dose level, with the goal to maximise cumulative viral editing to achieve undetectable levels of HBsAg.

PBGENE-HBV utilises ARCUS gene editing to target the root cause of chronic HBV infection

Chronic HBV affects approximately 300 million people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma. Current standard-of-care treatments suppress viral replication but rarely achieve functional cure.

PBGENE-HBV comprises a meganuclease-encoding mRNA encapsulated in a LNP and is designed to eliminate covalently closed circular DNA (cccDNA) and inactivate integrated HBV DNA; these are the persistent forms of the virus that serve as templates for viral replication and antigen production. By targeting cccDNA and integrated HBV DNA, Precision’s approach aims to address the root cause of chronic HBV infection.

The ELIMINATE-B trial is currently enroling HBeAg-negative chronic HBV patients at sites in Moldova, Hong Kong, and New Zealand, with plans to expand to the United States and United Kingdom. According to its press release, Precision expects to provide additional administrations at the current dose level and subsequently escalate to higher doses to define the optimal regimen. More detailed clinical data from the ELIMINATE-B trial is expected throughout 2025.

The latest clinical data represents the second clinical validation of Precision’s ARCUS in vivo gene editing platform this year, following recent positive clinical data from the OTC-HOPE study conducted by Precision's partner iECURE for ornithine transcarbamylase deficiency.

AccurEdit reports positive clinical data for single-dose gene-editing therapy in hypercholesterolemia

Last week, AccurEdit Therapeutics shared promising clinical data from its investigator-initiated trial of ART002, an investigational gene-editing therapy for heterozygous familial hypercholesterolemia (HeFH).

According to a press release, the data demonstrates that a single intravenous dose of ART002 significantly reduced low-density lipoprotein cholesterol (LDL-C) levels with excellent efficacy and safety profiles.

ART002 targets the PCSK9 gene to enable sustained cholesterol reduction

HeFH is a genetic disorder characterised by elevated LDL-C levels that significantly increase the risk of premature cardiovascular disease. Current treatments including statins and anti-PCSK9 antibodies require daily intake or regular injections, while newer siRNA therapies such as inclisiran require administration every six months with modest efficacy seen in long-term clinical studies.

ART002 utilises LNPs to deliver Cas9 mRNA and a single-guide RNA targeting human PCSK9. By silencing PCSK9, ART002 is designed to block its interaction with the LDL receptor (LDLR) thereby reducing LDLR degradation and increasing the number of LDLRs on hepatocyte surfaces to effectively reduce plasma LDL-C levels with a single dose.

The trial, carried out by The First Affiliated Hospital of Bengbu Medical University, enroled participants with significantly elevated baseline LDL-C levels. According to the press release, more than 60% of enroled patients had baseline levels exceeding 6.2 mM (240 mg/dL), which AccurEdit notes as being substantially higher than baseline levels in clinical trials of competing therapies.

In the medium- and high-dose groups, an average of approximately 90% PCSK9 protein knockdown was observed, with a maximum level of 93%, significantly surpassing the 69.8% mean reduction reported in clinical trials of the approved siRNA therapy inclisiran (2). At 12-24 weeks post-administration, most patients achieved LDL-C reductions exceeding 50%, with the highest reduction approaching 70%.

With the potential for long-term efficacy following a single dose, ART002 may reduce reliance on patient adherence, changing the long-term treatment landscape for patients with cardiovascular diseases and other chronic conditions.

Verve Therapeutics is pursuing a similar goal with its one-time, in vivo base-editing candidate VERVE-102. This candidate is being evaluated in the ongoing Heart-2 trial for the treatment of familial hypercholesterolemia or premature coronary artery disease. As of late 2024, VERVE-102 had been well-tolerated, with no serious adverse events and no clinically significant laboratory abnormalities observed. In a press release published last November, Verve Therapeutics indicated that it expects to share initial data from the Heart-2 clinical trial and an update on its PCSK9 programme in the first half of 2025.

We will continue to provide further updates on these trials as new data emerges.

For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.

References

1. Jiang Y, Chen S, Hsiao S, Zhang H, Xie D, Wang ZJ, Ren W, Liu M, Liao J, Wu Y. Efficient and Safe In Vivo Treatment of Primary Hyperoxaluria Type 1 via LNP-CRISPR/Cas9-mediated glycolate oxidase disruption. Mol Ther. 2024. Oct 8:S1525-0016(24)00663-4.

2. Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519.