Tune Therapeutics' TUNE-401, a First-in-Class Epigenetic Silencer, Enters Clinical Trials for Chronic Hepatitis B
核心洞察
Tune Therapeutics (搜索) has received approval to begin a Phase 1b clinical trial in New Zealand for TUNE-401, an epigenetic silencer targeting chronic hepatitis B (搜索) (HBV).
TUNE-401 aims to achieve a functional cure by permanently repressing both integrated HBV DNA (搜索) (intDNA (搜索)) and covalently closed circular DNA (cccDNA (搜索)) in hepatocytes.
Pre-clinical data presented at AASLD 2024 demonstrated near-complete repression of HBV DNA (搜索) and reduction of hepatitis B (搜索) surface antigen levels with TUNE-401.
Tune Therapeutics (搜索) is set to initiate a Phase 1b clinical trial of TUNE-401, a first-in-class epigenetic silencer, in adults with chronic hepatitis B (搜索) (HBV). The trial, approved by New Zealand's Medicines and Medical Devices Safety Authority (MEDSAFE), marks a significant step forward in the development of a potential functional cure for HBV, a global health challenge affecting an estimated 254 million people worldwide and causing 1.1 million deaths in 2022, according to the World Health Organization.
The Challenge of Chronic Hepatitis B
Hepatitis B (搜索) virus presents a dual challenge due to the persistence of covalently closed circular DNA (cccDNA (搜索)) and the integration of viral DNA into the host genome (intDNA (搜索)). cccDNA acts as a reservoir for new viral particles, while intDNA further complicates treatment. Current antiviral medications often fail to eradicate the virus completely, leading to chronic infection and potential progression to cirrhosis or liver cancer.
TUNE-401: Mimicking Natural Viral Control
TUNE-401 is designed to mimic a rare biological phenomenon observed in some chronic HBV patients, where the virus is sporadically controlled through epigenetic modifications. "Some patients can sporadically control the virus by putting on epigenetic marks to try to shut it down," explained Dr. Brian Cosgrove, bioengineer and principal scientist at Tune Therapeutics (搜索). "But it takes many, many years on antivirals, and it's very random and stochastic. Our idea was that we could programme in these repressive epigenetic phenotypes, shut down the virus, and produce a true functional cure."
Mechanism of Action
TUNE-401 comprises a catalytically-dead Cas9 (dCas9) fused to a methyltransferase and another epigenetic repressor. This combination targets a master controller sequence conserved between the intDNA (搜索) and cccDNA (搜索) of the virus across all known genotypes. Delivered via lipid nanoparticles, TUNE-401 contains an mRNA sequence encoding the epigenetic repressors and a guide RNA sequence targeting HBV. By remodelling this viral locus and programming a repressive state through DNA methylation and heterochromatin formation, TUNE-401 aims to inactivate all forms of the virus.
Pre-clinical Evidence
At the AASLD conference, Tune Therapeutics (搜索) presented pre-clinical data demonstrating that TUNE-401 leads to robust, durable, and precise suppression of HBV DNA (搜索) in both in vitro and in vivo models. The data showed almost complete (99.99%) repression of 3.5 kb HBV RNA from cccDNA (搜索) of infected primary human hepatocytes, with a corresponding reduction of extracellular hepatitis B (搜索) surface antigen levels. Durability experiments revealed virus silencing beyond 550 days following transient delivery to a cell line harbouring HBV, representing the persistence of repressive epigenetic marks through more than 275 rounds of cell division.
Clinical Trial Design
The Phase 1b study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TUNE-401 in adult participants with chronic HBV. The initial clinical trial site will be in Auckland, New Zealand, and led by Principal Investigator Dr. Ed Gane.