Dimmer Switch or On/Off Button? The Future of Gene Expression Control

Epigenome editing represents a cutting-edge field in genetic medicine that offers precise control over gene expression without altering the underlying DNA sequence. Unlike traditional genetic modification techniques, epigenome editing can be likened to a dimmer switch, allowing fine-tuned adjustments in gene expression levels, rather than simply turning genes on or off. Furthermore, the technique's non-invasive nature significantly mitigates the risks associated with off-target effects, promising safer and more precise interventions.

Several companies are at the forefront of harnessing epigenome editing for therapeutic purposes. Epic Bio, for instance, has developed the Gene Expression Modulation System (GEMS), a platform that combines a DNA-binding protein, a customized guide RNA, and various modulator proteins to enable powerful genetic medicine. Of particular interest is CasMINI, an ultra-small DNA-binding molecule exclusively licensed to Epic Bio, facilitating efficient work within human cells.

Epic Bio's promising candidate, EPI-321, has demonstrated the ability to halt muscle cell death with a favorable safety profile. The company is determined to advance this candidate to clinical studies, with plans to submit an investigational new drug application to the FDA and engage in discussions with German authorities for a clinical trial application. A first-in-human clinical trial for EPI-321 could potentially commence in 2024.
In another development, Chroma Medicine has secured substantial funding, totaling $260 million, to support its groundbreaking work in DNA methylation. Their innovative approach involves the use of a fusion protein that can transiently add or remove methyl marks on DNA. This technique offers durable responses without the need for DNA cutting or nicking, holding significant promise in the field of epigenetic medicine.
Chroma Medicine's two in vivo programs have demonstrated impressive gene silencing capabilities in mice, setting the stage for nonhuman primate trials. These programs leverage a combination of mRNA, guide RNA, and lipid nanoparticles to target complex disorders. One program focuses on tackling hepatitis B (HBV) infection, overcoming the challenges posed by HBV's integration into the genome. The epigenetic approach proves effective in silencing HBV, regardless of its episomal or integrated form. Additionally, Chroma Medicine's program targeting the PCSK9 gene, a well-studied target for hyperlipidemia, has achieved remarkable results. The company reported a 99% silencing of PCSK9 at ASCGT 2023, a breakthrough that underscores the potential of leveraging endogenous mechanisms for long-lasting gene expression regulation.
Navega Therapeutics is at the forefront of utilizing zinc finger nuclease and CRISPR-Cas technologies for precise epigenome regulation, paving the way for advanced therapies. Their primary focus lies in addressing various chronic pain conditions, such as chemotherapy-induced peripheral neuropathy. Additionally, Navega's pipeline encompasses treatments for neurological and ophthalmic diseases, promising innovative solutions for a range of medical challenges. Currently, Navega is actively engaged in researching and developing two undisclosed indications that showcase the potential for in vivo multiplexing in epigenome editing.
Tune, a biotech company, has developed the TEMPO platform, specializing in epigenomic control, allowing for precise gene expression regulation. TEMPO comprises two key components: a DNA-binding domain, enabling specific genomic targeting, and effectors that modify local epigenetic marks to modulate gene activity. At ASGCT 2023, Tune successfully employed TEMPO to stably repress the PCSK9 gene, leading to a substantial reduction in LDL-cholesterol levels in nonhuman primates, with a 75% decrease in serum PCSK9 and a 56% reduction in LDL-C levels over four months. This achievement marks a significant step towards durable epigenetic gene regulation, showcasing the platform's potential in large animal models and validating Tune's approach in the field of epigenetic medicine.

BioIntel360 anticipates that these advancements exemplify the transformative potential of epigenome editing in genetic medicine, offering new avenues for precision therapies with lasting effects while addressing complex medical challenges.