The final chapter in genomic medicines?

Tome Biosciences recently exited stealth mode with almost a quarter of a billion dollars in funding. The company has developed a new approach to gene editing, programmable genomic integration (PGI), which it says represents the final chapter in genomic medicines. 

We discussed the company’s formation and approach with the CEO and president of Tome Biosciences, Rahul Kakkar. 

Table of contents

    About Tome Biosciences

    The company launched in late 2023, although it was formed in 2021.

    Tome Biosciences was founded based on foundational science from a lab run by Jonathan Gootenberg and Omar Abudayyeh at MIT (Massachusetts Institute of Technology).

    The company raised $213 million in Series A and B funding from a range of investors prior to launch.

    What is programmable genomic integration?

    Programmable genomic integration enables the insertion of any DNA sequence, of any size, into any programmed genomic location. 

    “PGI represents the maturation of editing technologies, breaking current barriers in genomic medicines discovery,” Kakkar said.

    “It is revolutionary in that we can finally reprogram the human genome with an elegance and efficiency previously unimaginable. For patients with rare monogenic diseases, PGI allows for potentially curative treatments with a single drug per disease regardless of genetic heterogeneity, and for patients with more common disorders, PGI allows for the creation of cell therapies at the speed of biologics discovery with a complexity that enables the potential for broad use across human medicine.”

    Programmable genomic integration combines the site-specificity of CRISPR/Cas9 with enzymes capable of inserting or writing sequences of DNA. This includes entire genes, without the need for double-strand DNA breaks. Tome Biosciences’ most advanced PGI technology, integrase-mediated PGI (I-PGI), utilizes proprietary integrases.

    Just as a word processor can paste text anywhere in a document, I-PGI can insert large DNA sequences anywhere in the genome with unprecedented precision. I-PGI has demonstrated insertions of more than 30kb of genetic code with site-specificity in multiple different dividing and non-dividing cell types. Also, it can be multiplexed to enable complex cell engineering that will underpin the future development of cell therapies. 

    “I would consider (programmable genomic integration) the final maturation of genomic sciences for therapeutic purposes.”

    Rahul Kakkar, president and CEO, Tome Biosciences

    Programmable genomic integration technique: the ‘holy grail’

    Kakkar explained that, to date, in the field of genomic medicines, the manipulation of DNA has been limited.

    “We can randomly place pieces of DNA into the genome. We can place pieces of DNA with very little control through what’s called blunt end insertion. And we can cut DNA and break it through CRISPR-Cas9. And in some cases, we can put pieces of DNA in places that are natively recognized by the enzyme, what we call safe harbors. But to really have true user control, to empower a drug developer with the capability of editing the DNA as if it were computer code with true flexibility has eluded us. 

    “It really has been a holy grail that has eluded scientists until our founders devised this method of using not one enzyme but multiple enzymes in a specific configuration to be able to site-specifically put very, very large pieces of DNA into the genome.” 

    Kakkar added: “Once you can do that, it ushers in what I would consider the final maturation of genomic sciences for therapeutic purposes.”

    He said that there will still be important medicines that will do great good for patients that come out of the companies before Tome Biosciences. 

    “Many of those technologies, I think history will judge those as to be important advances along the way towards this idea of programmably and flexibly editing the DNA.”

    The role of CRISPR-Cas9

    Kakkar said CRISPR-Cas9 still has an important role to play.

    “All of the technologies that we have use CRISPR-Cas9 at their core. I think one way to think about it is CRISPR-Cas9 as the CPU of a computer. 

    “And in order to make a computer a desktop with certain capabilities versus a tablet, versus a laptop, versus a watch, versus an iPhone, you augment the core brain with other functionality. And that is what our technologies look like.”

    He noted that the novel drug platform that manipulates DNA is a new way of devising medicines.

    “What you’re really doing is creating a company whose pipeline is going to spread from the final evolution of what we traditionally have thought of as gene therapies all the way through to cellular therapies. Because when you can really recode DNA to do whatever you want it to do, you bring a whole new level of design power to cell therapies.” 

    The promise of programmable genomic integration in tackling diseases

    In the past, Kakkar explained, scientists and drug development experts have been limited in how they design and develop therapies based on DNA by the DNA editing and manipulating tools that they had. 

    “You can now insert DNA, whether it’s 10 base pairs, 100 base pairs, 1,000 base pairs, or 10,000 base pairs plus, which our various technologies allow us to do. Anything from 10 to tens of thousands of base pairs in a manner that is flexible in terms of size, flexible in terms of location. It’s not location that is restricted by the tools but restricted only by the imagination of the drug developer,” he said. 

    When there is a genetic disease, Kakkar said Tome Biosciences’ approach can fix the gene in situ. The DNA can then be repaired so that the cell will function as if it never had a broken gene to begin with. 

    “It’s not patching, it’s not a workaround for a genetic defect, as could be argued is the reality for current methods of gene therapy. That allows the cell to grow and develop and to regulate its own processes in a completely natural way.”

    Kakkar said cell therapies have provided revolutionary efficacy for patients with rare liquid tumors or hematologic malignancies. However, they have had a difficult time moving beyond that niche.

    “We believe that the reason for that is we haven’t been able to actually completely hijack the source code of a cell to have it do what we want it to do from a therapeutic standpoint, rather than what limited abilities we can give it when you can only do limited things with the DNA,” Kakkar continued.

    “And so this ability to really be size agnostic, high efficiency, and completely site-specific really allows us to repair genes in their place for genetic defects and to start to think about bringing cell therapies out of the corners of medicine more into the mainstream. Those are not capabilities that are possible with technologies coming before Tome, which are much more limited, before PGI.”

    Tome Biosciences’ pipeline

    Kakkar said that the company will divulge its pipeline, and the diseases it will be addressing, later in the year. 

    However, he revealed that on the integrative gene therapy side, the company be focusing on diseases of the liver.

    “Fortunately, we were able to scour the landscape of genetic defects of the liver and determine four or five diseases which are not similar to where most CRISPR-Cas9 companies are going, and we felt were truly conditions of unmet need where we could really do a service to those patients.

    “On the cell therapy side, we said, if we can truly, flexibly manipulate cells, reprogram them to be therapeutics in a way no one else can, that’ll only ever be academic unless we can create a truly differentiated medicine. And so we were excited to design our first cellular therapy, which is now in production, and believe that it has the potential to be a best in class for patients with autoimmune disease specifically.”

    Programmable genomic integration: the final chapter in genomic medicine

    The company has stated that programmable genomic integration is the final chapter in genomic medicine. Kakkar explained the reasoning behind the statement.

    “We thought long and hard before we decided to use that phraseology. Our chief science officer said, well, what tool are we missing after PGI? If you can now put any size piece of DNA into the genome exactly where you want it to go? It could be a portion of a gene, a gene, it could be a gene circuit, it could be multiple genetic elements. What are we missing at that point? 

    “It’s really hard to imagine what further capability a genomic drug developer could need. Now, not to say there aren’t improvements to be made. These systems are multi-component, they are complex, they are expensive to make, and certainly simplification of these systems is a laudable goal and something that our platform team works on as we think about generation two and three and beyond of PGI.”

    Kakkar concluded: “When I look at PGI specifically, I see it as that final maturation of the technologies, which will allow us to deploy genetic medicines, both cell and gene therapies, with the kind of breadth that so far have been relegated to biologic large molecules, chemical-based small molecules, and RNA therapeutics. And so, when we say the final chapter, we can’t think of another tool, another capability that we’re missing. Once you can flexibly edit the DNA, most of the other technologies look limited in some way. And so that’s why we call it the final chapter.” 

    To learn more about this topic

    Here are some links to more articles on the subject of gene and cell editing.

    Explore other topics: CRISPRGene editingLiver disease

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