Each year Nature Biotechnology profiles a company that has raised significant early-stage funding in the previous year. Tome Biosciences overcomes the limitations of base-prime editing to insert large DNA sequences into precise genomic locations.
Jonathan Gutenberg and Omar Abudayah have both always had their eye on the big challenges of genomic medicine. The two met as undergraduates at the Massachusetts Institute of Technology (MIT) in 2010 and now run the Abudayah Gutenberg Laboratory at Harvard Medical School, where they work on developing molecular tools to understand and treat age-related diseases. As doctoral students, working with CRISPR pioneer Feng Zhang at the Broad Institute, they began strategizing how to integrate DNA sequences of any size into the genome. Their efforts finally came to fruition in 2020, when the young scientists developed a gene-editing tool that promises to safely deliver DNA sequences of tens of thousands of base pairs into human cells. The two then founded Watertown, Massachusetts-based company, Torm Biosciences.
Jonathan Guttenberg (left) and Omar Abudayeh. Credit: Tome Biosciences
Tome raised $213 million in Series A and B funding in December 2023 and debuted with a mission to “write the final chapter in genome editing,” Gutenberg says. The company claims it can insert large DNA sequences at precise locations in the genome with a low risk of off-target effects. Ideally, this approach (called programmable genomic integration (PGI)) will overcome the limitations of base and prime editing, which are primarily effective for “diseases caused by single mutations,” says cardiologist and Tome CEO Rahul Kakkar. Tome instead aims to replace entire genes and treat diseases caused by more DNA defects.
Gutenberg and Abudaeh came up with the technique in 2019, when they were both McGovern Research Fellows at MIT. By that time, the two had already become close collaborators, publishing many papers together. One of their biggest goals was to precisely deliver large DNA sequences to specific locations in the genome while avoiding the possibility of cell damage. They had been using the original CRISPR-Cas9 system for genome editing, which had the drawback that the target sequence was only operational after the DNA double helix was broken. Breaking double-stranded DNA carries several risks, including the possibility of causing unintended genetic modifications or even cell death. So the two researchers tried other techniques and eventually came up with a solution. Instead of cutting both strands of the double helix, they employed a new CRISPR-Cas9-based system that creates single-stranded DNA breaks at specific points in the genome. Then, a biochemical process is used to integrate the DNA payload and repair the broken strand, resulting in precise gene insertion. The good news is that single-strand breaks “can be easily repaired by the cell’s DNA repair mechanisms without causing any adverse effects,” says Sadiq Kassim, chief technology officer for genomic medicine at Danaher, a Washington, DC-based life sciences and diagnostics company.
Gutenberg and Abudayeh began developing Tome while refining the technique, which they called programmable addition with site-specific targeting elements (PASTE). “We felt it was time to raise capital to really scale this beyond our own lab’s resources,” Abudayeh says. Investors including Arch Ventures and Longwood Fund provided initial backing, and then Kakkar joined in 2021, shortly after his company, Pandion Therapeutics, was acquired by Merck for $1.85 billion. Kakkar says he got involved after reading a preprint that Gutenberg and Abudayeh had recently posted to bioRxiv, a research server that has not yet been peer-reviewed. In it, the two scientists explain that they have successfully used PASTE to deliver sequences up to 36,000 base pairs long into human and other cell types. The paper was published in Nature Biotechnology in 2022. “We were blown away by how cool this technology is, but also by the impact it could have on both cell and gene therapy,” Kakkar says. “It’s not often that you come across a technology that can fundamentally change two incredibly important areas – drug discovery and development. I was excited to be a part of it.”
After consulting with academic experts, Tome settled on a pipeline focused on gene therapies for monogenic liver diseases and cell therapies for autoimmune diseases. There are several reasons for choosing monogenic liver diseases, one of which is the lack of definitive treatments, says Kucker. Pediatric monogenic liver diseases, particularly severe ones, are not well controlled with current treatments and have a high incidence of side effects. Tome’s treatment strategy is to replace the defective gene with a normal copy in the correct location, allowing children with these diseases to “live normal lives and thrive,” Kucker says. Moreover, the delivery challenge is easier to handle in the liver than in other tissues, adds Michelle Avery, Tome’s vice president of corporate affairs. Tome uses viral vectors to deliver a normal copy of the defective gene and lipid nanoparticles to deliver a genome editing device that inserts the normal gene where it is needed. This approach allows the expression of the editing mechanism to be time-limited, thereby limiting safety risks that would arise if the mechanism remained in the cells for a long time, says Kucker. Delivery to the cell therapy platform is done by in vitro electroporation. The focus on autoimmune diseases is based on recent evidence that cell therapy has the potential to bring about long-term remission of diseases such as lupus.
The company is working on genome editing in multiple ways. One is an industrialized version of PASTE, which uses integrase for payload insertion, and another is coming with Tome’s recent acquisition of Replace Therapeutics, a deal worth up to $185 million that gives it access to the company’s ligase-mediated technology. The Replace acquisition enables “what we now call ligase-mediated PGI,” Kakkar says. “Again, it’s about inserting DNA in a specific way with high efficiency, but this time with ligase instead of integrase.” Kakkar wouldn’t elaborate further on the pipeline, saying only that the gene therapy and cell therapy platforms are “going neck to neck.”
Philip Santangelo, a professor of biomedical engineering at Emory University and Georgia Institute of Technology, calls Tome’s approach innovative and exciting. But like other companies in the genome editing field, Tome faces complex implementation challenges and will need to demonstrate safety and efficacy, Santangelo says. “If we can solve these other problems, I think the potential for therapy is very high,” he says. Hashim, who also sits on Tome’s scientific and technical advisory board, adds that the company will need to show it can control copy number expression. “The FDA will want to know how many copies of a particular gene are expressed in the cell,” Hashim says, because overexpression can cause tumors and other safety issues.
Still, the ability to insert DNA sequences at scale opens the door to solving many unmet clinical needs, such as rare diseases caused by many different mutations affecting a particular gene. “We can now make drugs that work regardless of the mutation because we’re just replacing the entire genetic console,” Abdaye says. “This makes drug development more economically feasible and helps us reach more patients, so it’s a win-win for everyone.”
