Tune Therapeutics Presents First Data Supporting TUNE-401: a First-in-Class Epigenetic Silencer for Hepatitis B
NOTE: Tune Therapeutics is a Duke University start-up and Duke Capital Partners portfolio company developing epigenetic editing spun out of the lab of co-founder Professor Charles Gersbach (BME, Pratt). Duke Fuqua alum Matt Kane is CEO and Duke Biochemistry postdoc Derek Jantz is CSO. This press release first appeared on BusinessWire.
Data shows deep repression of HBV both in primary cells and ‘gold standard’ humanized mouse model
Therapeutic targets a single “master controller” sequence to silence all forms of the virus
Approach offers a path to functional cure for HBV
December 06, 2023 08:00 AM Eastern Standard Time
DURHAM, N.C. & SEATTLE–(BUSINESS WIRE)–Leading epigenome editing company Tune Therapeutics presented data in support of its chronic Hepatitis B Virus (HBV) program, demonstrating the ability to durably silence essential mechanisms of viral replication and persistence across a range of model systems.
TUNE-401 represents a fundamentally new approach to HBV treatment, in that it utilizes Tune’s precision genetic tuning platform, TEMPO, to inactivate viral DNA integrated into host chromosomes, while simultaneously silencing the extra-chromosomal, cccDNA “viral factories” necessary for sustained HBV infection. Importantly, the TEMPO platform does this via epigenetic processes, and without cutting, damaging, or altering genomic DNA sequences in any way.
The ability to suppress the virus in both contexts – both within and outside the host genome – is an established prerequisite for control of the virus in chronic HBV patients, and this new epigenetic silencing approach offers a pathway toward a functional cure for HBV as a standalone therapy.
The Tune HBV data, shared for the first time at the 2023 HepDART hepatology conference, showed:
- near-complete repression of viral DNA in primary human hepatocytes and cell lines in vitro, with ongoing durability now beyond 550 days, and more than 275 cell doublings
- similarly high levels of repression in successfully epi-edited cells in vivo, using chimeric, true-infection mouse models
- highly specific targeting and methylation by TUNE-401 for both integrated virus and cccDNA – with little or no expression change in non-targeted genes
Moreover, these results were achieved via a single target sequence, common to all viral contexts and locations within the cell, and highly conserved across HBV genotypes.
“We used TEMPO to screen for epigenetic repression targets that are active in cccDNA, and also in integrated HBV DNA,” explained Principal Scientist Brian Cosgrove, who presented the data at HepDART. “Through the richness of these data sets, we found multiple repression candidates that worked well in both contexts. The most compelling targets went on to yield near-complete repression of viral DNA in primary human hepatocytes, when corrected for per-cell delivery efficiency limits.”
In validating this target in vivo, Tune took care to select a comprehensive and informative HBV infection model featuring humanized FRG mice.
“We know from clinical research,” said Cosgrove, “that less than 5 percent of chronic HBV patients achieve full viral clearance and cure. Many who do, however, show epigenetic inactivation of the cccDNA. And while a variety of in vivo models exist for HBV infection, very few allow for the effective study of HBV regulation in its natural, extrachromosomal (cccDNA) context. The chimeric FRG mouse model does just that.”
Chimeric FRG mice are created via the ablation and replacement of mouse liver cells with transplanted, human hepatocytes – effectively “humanizing” the liver. As such, they represent the gold standard for assessing the dose and efficacy for liver-directed therapeutics ahead of human clinical trials. When tested in this model system, TUNE-401 showed high repression in delivered cells.
Though no large animal model is available for HBV, Tune has demonstrated durable, liver-directed epi-editing of non-human primates (NHPs) using a surrogate target (PCSK9) and the same, essential mode of action – targeted DNA methylation.
“Based on the breadth of our preclinical data, we have every reason to believe that this novel therapeutic strategy will translate,” says Derek Jantz, Chief Scientific Officer at Tune Therapeutics. “We sincerely hope that this will revitalize the field and lead to the standalone functional cure that HBV patients have been waiting for.”
Tune expects its HBV program to enter the clinic by the end of 2024, under the guidance of leading international clinical investigator Dr. Edward Gane.
About Tune Therapeutics
Armed with its powerful and innovative genetic tuning platform (TEMPO), Tune Therapeutics aims to bring gene, cell, and regenerative therapies into a new era of human medicine – expanding their range of application to common, chronic and age-related diseases that are straining healthcare systems and limiting human healthspan on a global scale.
Tune is currently hiring for additional members to join the team. For more information, please visit https://tunetx.com/join-the-band/.
About TUNE-401
TUNE-401 is a first-in-class investigational product candidate for the treatment of Hepatitis B (HBV) infection. TUNE-401 utilizes Tune’s TEMPO platform to epigenetically silence viral HBV DNA in host chromosomes, while simultaneously silencing the extra-chromosomal, cccDNA “viral factories” necessary for sustained HBV infection. Lipid nanoparticle technology for TUNE-401 has been provided by Acuitas Therapeutics Inc.
Contacts
Glenn Murphy, Director of Communications
glenn.murphy@tunetx.com
(919) 274-6922