Prolonged Epigenetic Suppression in Mice Strengthens Argument for Therapeutic Applications

Recent mouse study findings suggest that epigenetic gene silencing could effectively hinder a target gene for a substantial duration, potentially nearing a year. Dr. Angelo Lombardo, leading the research at Vita-Salute San Raffaele University, underscored the significance of this revelation in an interview with Fierce Biotech Research, marking it as the inaugural documented instance of achieving enduring gene suppression through epigenetic means.

Epigenetic silencing, akin to gene editing, directly influences gene activity. However, it diverges from gene editing as it doesn’t alter the DNA sequence but rather modifies gene expression by attaching compounds, such as methyl groups, which effectively inactivate the gene. This method offers advantages, including the reversibility of modifications and a decreased risk of DNA damage.

Dr. Lombardo elaborated that akin to gene editing, epigenetic modifications are inherited as cells divide but can also be reversed, as evidenced in earlier cell line studies conducted by his team. He stressed that their approach targets compounds governing gene expression rather than directly altering the genome.

In their recent investigation, Lombardo’s team centered on altering the PCSK9 gene in liver cells. PCSK9 controls a protein regulating LDL cholesterol levels, commonly referred to as “bad” cholesterol due to its association with arterial blockage and heart disease.

Around two decades ago, researchers stumbled upon an exceedingly rare mutation naturally suppressing the PCSK9 gene, offering protection against heart disease. This discovery prompted substantial research endeavors aimed at developing therapies targeting PCSK9 to reduce cholesterol levels, resulting in the emergence of novel drugs and gene editing therapies. Epigenetic therapies, perceived as less hazardous than gene editing, have also emerged as a promising avenue in this endeavor.

The study’s results showcased that a solitary dose of epigenetic modifiers administered via lipid nanoparticles decreased PCSK9 protein levels in healthy mice by approximately half for up to 330 days, accompanied by a corresponding reduction in cholesterol levels. Refinements to the technology achieved even more significant reductions in PCSK9 levels, nearing those achieved through gene editing using CRISPR-Cas9. The treated mice exhibited only transient alterations in liver enzyme levels, with no other notable side effects reported by the researchers.

The study establishes proof-of-concept of enduring and effective epigenetic suppression in vivo, offering encouraging prospects for gene therapy. Although the study didn’t directly assess therapeutic benefits, it presents promising indicators for treatments under development by companies like Chroma and Tune Therapeutics. Tune Therapeutics notably demonstrated the efficacy of its epigenetic TEMPO platform in silencing PCSK9 and lowering LDL cholesterol levels in primates, indicating the technology’s potential across various diseases.

Dr. Lombardo expressed optimism regarding the expanding applications of epigenetic suppression, envisioning its utilization in various domains such as T-cell engineering for cell therapies and editing hematopoietic stem cells. Despite challenges in effectively delivering therapies to organs beyond the liver using lipid nanoparticle-based systems, he remains dedicated to exploring new avenues for epigenetic manipulation and gene therapy applications, including targeting genes in the central nervous system.

The study provides evidence of the efficacy and durability of epigenetic suppression, offering promising avenues for gene therapy and its potential in combating a broad spectrum of diseases.

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