The field of genetic medicine aims to address diseases by directly modifying an individual’s DNA. Precisely altering the genetic code to introduce therapeutic benefits is a central challenge. Current methods often face limitations in inserting specific genetic material accurately or durably. Tome Therapeutics is developing new approaches to overcome these obstacles, aiming for more precise and controlled alterations to the human genome.
The Core Technology: Programmable Genomic Integration
Tome Therapeutics’ foundational innovation is Programmable Genomic Integration (PGI), a technology licensed from the Massachusetts Institute of Technology. PGI differs from traditional gene editing methods, such as CRISPR, by precisely inserting large genetic sequences into specific genomic locations. This process avoids creating double-strand DNA breaks, a common feature of many existing gene editing tools that can lead to unintended genetic alterations.
PGI uses a suite of technologies to insert any DNA sequence into a chosen genomic location. One key component is integrase-mediated PGI (I-PGI), which uses proprietary integrases for high-precision DNA insertion. This allows targeted integration of large sequences, up to 36,000 base pairs, into various cell types.
Another PGI technology is ligase-mediated PGI (L-PGI), suited for integrating smaller DNA sequences, from 1 to hundreds of base pairs. Both I-PGI and L-PGI enable the precise placement of therapeutic genes, allowing natural cellular processes to regulate their expression.
Enhancing Precision and Control
Tome Therapeutics’ PGI approach offers enhanced precision in gene insertion, leading to more stable and durable therapeutic effects. This precise targeting helps ensure the therapeutic gene is integrated into a desired location, minimizing the risk of disrupting other functional genes.
Tome’s in vivo capabilities address current limitations in gene therapy delivery. The company has demonstrated the ability to achieve therapeutically-relevant targeted gene integration and functional protein expression in vivo in non-human primates. This indicates the potential for direct administration of the therapy into the body, which could simplify treatment protocols and expand the reach of gene therapies to more patients. The technology aims to overcome transient gene expression by integrating genes directly into the host genome for sustained effect.
The PGI platform also provides more controlled therapeutic interventions by allowing the insertion of large DNA sequences that can include elements like “safety switches” or other protective characteristics. This capability can boost the effectiveness or safety of cell therapies by enabling precise control over gene expression and function within modified cells. The technology has also shown efficient multiplex editing and integration of large DNA sequences with functional gene expression in iPSC-derived NK cells, suggesting its versatility for complex cell engineering applications.
Target Diseases and Potential Applications
Tome Therapeutics is focusing its programmable genomic integration technology on a range of genetic disorders and therapeutic areas. The company initially aims to develop gene therapies for monogenic liver diseases, conditions caused by a single gene defect. This focus includes diseases challenging for existing gene editing technologies.
The PGI platform also applies to cell therapies for autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, where modifying B cells can reduce autoimmune activity. The technology’s ability to precisely insert large DNA sequences is relevant for diseases caused by mutations in very large genes, like Duchenne muscular dystrophy, which often require workarounds with other gene editing methods.
Tome Biosciences’ lead programs include an integrative gene therapy for phenylketonuria (PKU) and a cell therapy for renal autoimmune diseases using CD19/BCMA CAR-iNK cells. Their platform aims to develop new treatments for conditions currently underserved by existing therapies, offering the prospect of curative treatments with a single drug per disease.