Jonathan Gootenberg and Omar Abudayyeh have both always had an eye on big challenges in genomic medicine. The pair met as Massachusetts Institute of Technology (MIT) undergraduates in 2010 and today run the Abudayyeh-Gootenberg lab at Harvard Medical School, developing molecular tools for understanding and treating age-related diseases. As PhD students working with CRISPR pioneer Feng Zhang at the Broad Institute, they began strategizing on ways to put DNA sequences of any size into the genome. Those efforts ultimately paid off in 2020, when the young scientists developed a gene-editing tool that offers the promise of safely delivering DNA sequences numbering tens of thousands of base pairs into human cells. They subsequently founded Tome Biosciences, based in Watertown, Massachusetts.

Jonathan Gootenberg (left) and Omar Abudayyeh. Credit: Tome Biosciences

Tome debuted in December 2023 with $213 million in series A and B funding and a mission to “write the final chapter in genome editing,” Gootenberg says. The company claims it can insert large DNA sequences into 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 useful mostly “for diseases driven by single mutations,” says Rahul Kakkar, a cardiologist and Tome’s CEO. Tome aims instead to replace entire genes and thereby treat diseases caused by more numerous DNA defects.

Gootenberg and Abudayyeh first conceived of the approach in 2019, when they were both McGovern fellows at MIT. By then, the pair were already close collaborators who had jointly published many papers. One of their top goals was to deliver large DNA sequences precisely into specific locations in the genome while avoiding the potential for cell damage. They were working with the original CRISPR–Cas9 system for genome editing, but this has the drawback that target sequences are exposed for manipulation only after the DNA double helix has been broken. Double-stranded DNA breaks pose several risks, including the potential to create unintended genetic modifications and to cause cell death. So the two researchers experimented with other approaches and in time hit on a solution: instead of snipping both strands of the double helix, they employed a novel CRISPR–Cas9-based system that creates single-stranded DNA breaks at specific points in the genome. Biochemical processes are then harnessed to integrate DNA payloads and repair the broken strands, resulting in precise genetic insertions. Fortunately, single-strand breaks “can be easily fixed by the cell’s DNA repair mechanisms without causing adverse effects,” says Sadik Kassim, chief technology officer of genomic medicine at Danaher, a Washington, DC-based life sciences and diagnostics company.

While refining the method, which they called programmable addition via site-specific targeting elements (PASTE), Gootenberg and Abudayyeh set out to create Tome. “We felt it was time go beyond the resources of our own lab and raise money to really scale this up,” Abudayyeh says. Investors including Arch Venture and the Longwood Fund provided initial support, and then Kakkar joined in 2021, shortly after his company Pandion Therapeutics was acquired by Merck & Co. for $1.85 billion. Kakkar says he came on board after reading a preprint that Gootenberg and Abudayyeh had recently posted to bioRxiv, a server for research that has not yet been peer reviewed. In it, the two scientists described using PASTE to successfully deliver sequences as long as 36,000 base pairs into human and other cell types. The paper was published in Nature Biotechnology in 2022. “I was struck not just by the elegance of the technology but also its impacts on both cell and gene therapy,” Kakkar says. “We don’t often come across techniques that can fundamentally transform two very important areas of drug discovery and development. I was elated that this was something I could get involved in.”

After consulting with academic experts, Tome settled on a pipeline focused on gene therapy for monogenic liver diseases and cell therapy for autoimmune disorders. They selected monogenic liver diseases for several reasons, one being that they lack definitive curative treatments, Kakkar says. Severe pediatric monogenic liver diseases in particular are poorly controlled by current therapies, which also have high rates of side effects. Tome’s therapeutic strategy is to replace defective genes with normal copies in their correct locations, so that children with these conditions “can grow up living normal lives,” Kakkar says. Moreover, delivery challenges are more tractable in the liver than they are in other tissues, adds Michelle Avery, Tome’s vice president for corporate affairs. Tome uses a viral vector to deliver a normal copy of the defective gene and a lipid nanoparticle to deliver the genome editing machinery that inserts the normal gene where it is needed. The approach allows time-limited expression of the editing machinery, Kakkar says, thereby limiting safety risks that can result if that machinery remains too long in a cell. Delivery for the cell therapy platform is achieved with electroporation ex vivo. The focus on autoimmune diseases was based on recent evidence that cell therapies might result in long-term remissions in diseases such as lupus.

The company tackles genome editing in several ways: one is an industrialized version of PASTE, which relies on integrases for payload insertion, and the other was facilitated by Tome’s recent acquisition of Replace Therapeutics, in a deal worth up to $185 million that provides access to that company’s ligase-mediated technology. The Replace acquisition enables “what we now call ligase-mediated PGI,” Kakkar says. “Which refers again to inserting DNA in a specific manner at high efficiency, but this time using ligases instead of integrases.” Kakkar would not discuss the pipeline in further detail, saying only that the gene and cell therapy platforms are progressing “neck and neck.”

Philip Santangelo, a professor of biomedical engineering at Emory University and Georgia Tech, describes Tome’s approach as innovating and exciting. But like other companies in the genome editing field, Tome also confronts complex delivery challenges, Santangelo says, and a need to demonstrate safety and efficacy. “I think the therapeutic potential is very high, as long as they solve these other problems,” he says. Hassim, who is also a member of Tome’s Science and Technology Advisory Committee, adds that the company needs to show it can regulate copy number expression. “The FDA will want to know the number of copies that are expressed of a particular gene within the cell,” Hassim says, given that overexpression can cause tumors and other safety problems.

Still, the capacity for large DNA sequence insertions opens doors to solving many unmet clinical needs — for example, for rare diseases caused by a large number of different mutations that affect a particular gene. “You could now have a drug that works regardless of what mutation someone has because you’re just replacing the entire gene console,” Abudayyeh says. “It makes drug development more economically feasible, and it reaches a lot more patients. So, it’s a win for everybody.”