SynGenSys Launches Synthetic Promoter Library for Liver-Targeted Gene Therapies

Sheffield-based biotech company SynGenSys has released a new library of synthetic promoters designed to improve precision in liver-directed gene therapies, addressing a persistent challenge in the development of in vivo treatments.

The Liver.SET™ library offers researchers a collection of compact, synthetic promoters engineered to drive gene expression specifically in liver tissue while minimising unwanted activity in muscle, a common source of off-target effects in systemically delivered gene therapies. The promoters have been validated in both cell culture and animal models.

Addressing manufacturing and delivery constraints

One notable feature of the Liver.SET promoters is their low activity in HEK293 cells, the workhorse cell line used to produce adeno-associated virus (AAV) vectors. Premature expression of therapeutic genes during vector manufacturing can reduce yield and quality, so promoters that remain largely silent during production offer a practical advantage.

The library's promoters are also designed with compact sequences, which matters when working within the strict packaging limits of AAV vectors - typically around 4.7 kilobases. Every nucleotide counts when fitting a promoter, therapeutic gene, and regulatory elements into such a constrained space.

According to SynGenSys, the modular architecture of these promoters allows for rapid customisation, giving developers flexibility to tune expression levels and regulatory behaviour rather than being locked into the fixed characteristics of naturally occurring liver promoters.

Building on a platform approach

Liver.SET is the second tissue-specific promoter library from SynGenSys, following NK.SET, which targets natural killer cells for cancer immunotherapy applications. The company's proprietary computational platform combines informatics with design algorithms to generate synthetic promoters tailored to specific tissues and therapeutic contexts.

The release signals the company's intention to expand into additional tissue targets. SynGenSys has indicated that promoter libraries for muscle, retina, and central nervous system applications are in development, alongside custom design services for bespoke therapeutic programs.

Dr. Mike Daniels, Chief Commercial Officer at SynGenSys, commented: "The launch of Liver.SET™ represents another significant milestone for SynGenSys, demonstrating that our platform can deliver synthetic promoter solutions for real gene therapy development needs. We see this as a key enabler for in vivo gene therapies, and a reliable, validated starting point for deeper collaboration with developers seeking to design novel therapeutics with enhanced precision and safety."

Why liver specificity matters

The liver is a major target for therapeutic transgene expression in gene therapies of inherited diseases such as Haemophilia, Phenylketonuria, and Fabry disease, and in cancer and hepatitis. However, systemic delivery of AAV vectors often results in transduction of multiple tissues, particularly skeletal and cardiac muscle. This can dilute therapeutic effect, raise safety concerns, and complicate dosing strategies.

Promoters with strong tissue specificity allow therapeutic genes to be expressed where they're needed while remaining transcriptionally silent elsewhere. This can potentially reduce the vector doses required and improve the therapeutic index, particularly important given ongoing concerns about AAV-related toxicity at high doses.

The demonstrated specificity in the Liver.SET library, particularly the active de-targeting of muscle tissue, could prove valuable as developers work to improve the safety profiles of next-generation gene therapies. Whether these synthetic promoters will outperform optimised natural promoters in clinical settings remains to be seen, but the flexibility and customisability they offer represent a meaningful addition to the gene therapy toolkit.