Tome Biosciences Showcased Genomic Integration Tech at ASGCT

Tome Biosciences, Inc., a pioneer in programmable genomic integration (PGI), has recently showcased notable advancements in integrative gene and cell therapy at the 27th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) held in Baltimore, MD. The company's Chief Scientific Officer, John Finn, PhD, emphasized the comprehensive potential of PGI technologies, ranging from efficient and multiplex editing of induced pluripotent stem cells (iPSCs) and hematopoietic stem cells (HSCs) to targeted gene integration in non-human primates.

Tome Biosciences has developed two core technologies for PGI: integrase-mediated PGI (I-PGI) and ligase-mediated PGI (L-PGI). The I-PGI method is designed for the integration of large DNA sequences exceeding 1,000 base pairs. It functions by introducing a unique sequence into the genome at a specific location, which then acts as a marker for a specialized integrase to insert the desired DNA sequence. On the other hand, L-PGI is suitable for smaller DNA sequences ranging from 1 to several hundred base pairs and can precisely insert any small template DNA sequence into the genome. Both technologies offer the advantage of editing the genome without the need for double-stranded DNA breaks.

During the ASGCT meeting, Tome Biosciences provided updates on their lead programs, particularly focusing on integrative gene therapy for phenylketonuria (PKU) and a cell therapy program using CD19/BCMA CAR-iNK for treating renal autoimmune diseases.

For the PKU program, the company reported significant progress in liver technical development. By employing I-PGI, they demonstrated successful gene integration and functional gene expression at multiple loci in primary human hepatocytes and in vivo in mice and non-human primates. The early data from non-human primates indicated potentially curative editing efficiencies.

In their CD19/BCMA CAR-iNK program, the company achieved efficient I-PGI integration of a 12,000 base-pair sequence into iPSCs. The differentiated iNK cells exhibited functional gene expression aimed at improving the efficacy and convenience of autoimmune cell therapy, with the added capability of re-dosing and reversing treatment. Preclinical data presented included evidence of CD19 targeting in mice and the effective killing of B cells in blood samples from lupus patients.

Furthermore, Tome Biosciences addressed previously unreported challenges associated with reverse transcriptase-mediated insertion of long sequences in non-dividing rodent cells and proposed potential solutions. The company also highlighted the proficiency of I-PGI in editing iPSCs and HSCs, successfully integrating over 30,000 base pairs and executing multiplexing across four genes at different loci. This capability facilitates the rapid development of complex cell circuitry.

Additionally, the company has developed proprietary assays to detect potential off-target effects of integrases, such as double-stranded breaks (DSBs), insertions/deletions (indels), cryptic integrations, and chromosomal rearrangements. L-PGI also demonstrated high-fidelity editing of primary human hepatocytes in vitro across multiple therapeutically relevant genomic loci compared to DNA edits using reverse transcriptase.

Tome Biosciences continues to advance its mission of delivering cures through precise cell and integrative gene therapies, leveraging their innovative PGI technologies to achieve significant milestones in the field of genomic medicine.