Beyond CRISPR: Brink Therapeutics raises $4 million with engineered recombinases

A fresh take on gene-editing, centered on engineered recombinases, emerges as Brink Therapeutics, a Paris-based biotech startup, secures €3.5 million ($4 million) in seed funding with Kuma Partners and Breega as lead investors to advance its platform. 

While CRISPR/Cas9 has been the cornerstone of gene editing, it faces challenges such as off-target effects and difficulties with in vivo applications. Brink Therapeutics aims to address these limitations by developing programmable recombinases through directed evolution and AI-driven design.

Could the emergence of companies like Brink Therapeutics indicate a broader shift in the gene-editing landscape?

The limits of CRISPR and the rise of recombinases

Over the past decade, CRISPR/Cas9 has become synonymous with gene editing for its ease of use and broad applicability. But when it comes to therapeutic use, especially inside the human body, its limitations have become increasingly apparent. 

“Since the initial application of natural restriction enzymes in the 1970s, site-specific nucleases such as Zinc Finger Nucleases, TALENs and now CRISPR have been the cornerstone of site-specific DNA modification. However, nucleases have a fundamental shortcoming, they have evolved to defend host cells against mobile genetic elements (MGEs) like viruses by degrading their DNA in a targeted manner. If we want to make a substantial modification such as the insertion of a therapeutic transgene into a DNA site of interest, we have to rely on additional machinery such as a host cell’s endogenous DNA repair pathways to complete the edit,” explained Jonathan Naccache, co-founder and chief executive officer (CEO) of Brink Therapeutics.

Naccache also explained that the double-strand breaks in DNA that methods like CRISPR generate can be toxic for cells and result in imprecise, heterogeneous edits and difficult-to-detect off-target edits.

These difficulties led scientists and startups to explore alternative approaches. Among the most promising are recombinases: enzymes that can precisely rearrange or insert DNA sequences without introducing double-stranded breaks. Unlike CRISPR, which acts like molecular scissors, recombinases operate more like precision editors, capable of integrating DNA segments in a more controlled way.

“Site-specific recombinases (SSRs) are nature’s genome editors, evolved to allow MGEs to proliferate successfully within host cells, for example, by integrating their DNA into the genome of the host cell. These enzymes are able to self-sufficiently cut-and-paste DNA sequences in a precise, site-specific manner, and so are often the enzyme of choice in contexts where their cognate target sites can be pre-introduced into a genome, such as in cell and animal models,” said Naccache.

Historically, however, recombinases have been limited by their lack of programmability. While effective in bacterial systems or specific genomic contexts, they’ve been difficult to adapt to therapeutic targets in human cells. That’s starting to change. Recent research, such as work by the Arc Institute published in Nature in 2024, has shown how recombinases can be guided to specific sites using engineered “bridge RNAs,” unlocking new potential for targeted gene integration.

In parallel, companies like Tessera Therapeutics are developing “gene writing” platforms based on mobile genetic elements, including recombinases, that aim to precisely insert DNA into the genome without relying on CRISPR. There is a growing interest in gene editing tools that go beyond the current CRISPR paradigm.

Brink Therapeutics is part of this movement. Rather than trying to improve CRISPR itself, the French startup is developing a platform to make recombinases programmable, using techniques like directed evolution and AI-powered enzyme design. 

Brink Therapeutics’s approach: Making recombinases programmable

While many gene editing startups focus on refining CRISPR, Brink Therapeutics is taking a different path. The French company uses directed evolution, a method that mimics natural selection in the lab to improve proteins over successive cycles. To speed things up, Brink also uses a technique called in vitro compartmentalization, a way of running billions of enzyme reactions in parallel inside microscopic droplets. It’s a miniaturized system that accelerates how quickly recombinases can be tested and optimized.

By repeating these cycles, Brink can evolve recombinases that target specific genomic sites with high precision. The resulting data, on which enzymes work, and why, is being compiled into a proprietary library that will also feed into AI-driven design tools. This opens the door to eventually designing enzymes computationally before testing them in the lab, speeding up discovery even further.

“The key to Brink’s tech platform for recombinase programming is the scale of screening and data generation it is capable of. The combination of our in vitro Directed Evolution, metagenomic discovery and genAI platforms allows us to rapidly screen and capture activity data for billions of synthetic and natural recombinase sequences against diverse DNA target sequences, while continually learning from the results,” said Harry Kemble, Brink Therapeutics’s co-founder.

The first application Brink Therapeutics chose is in CAR-T cell therapy, where patient immune cells are genetically modified to fight cancer. These therapies have shown impressive results in blood cancers, but their manufacturing remains complex and expensive.

“CAR-T therapies for hematological cancers is the most mature market for gene insertion, already weighing $3 billion per year, but still with enormous room for expansion, only a small fraction of eligible patients currently receive it due to ex vivo manufacture scalability issues. It therefore presents an ideal application for Brink’s recombinases in the framework of a Cell & Gene Therapy already known to be effective, before moving into riskier, less established markets like monogenic diseases,” explained Kemble.

Brink hopes that by enabling precise DNA insertion in vivo, its technology could simplify the process and make CAR-T more accessible. Long term, the platform could support a broader range of genetically modified cell therapies, from solid tumors to rare diseases, anywhere a safe, efficient gene insertion tool is needed.

Brink Therapeutics, and the future of programmable gene editing

With its €3.5 million ($4 million) seed round, Brink Therapeutics plans to scale its team and push its platform toward key proof points. The immediate goal is to validate five recombinases by 2026, demonstrating their ability to make precise and safe DNA edits in human cells. The company is also building a library of data that will underpin AI-assisted enzyme design.

If successful, Brink hopes to extend its platform well beyond CAR-T therapies. Its long-term ambition is to enable in vivo genome editing, editing directly inside the body, which could simplify manufacturing, lower costs, and open up treatment for conditions currently out of reach for conventional gene therapy.

Brink isn’t alone in this space. U.S.-based Tessera Therapeutics is working with recombinases to insert therapeutic DNA without relying on CRISPR. Seamless Therapeutics, based in Germany, is also working on reprogramming recombinases to target specific sequences, aiming to make them as flexible as CRISPR tools but with fewer risks. 

These efforts are still isolated but as they add up they reflect a broader movement to rethink the gene editing toolkit. With CRISPR showing its limits in certain settings, a new generation of programmable, enzyme-based platforms is emerging and Brink Therapeutics is one of the startups helping lead that charge.

According to Naccache, recombinase-based editing isn’t just an incremental improvement in gene editing, it’s a paradigm shift. “Inserting large DNA sequences in vivo at high efficiency and precision is out of reach to existing technologies. Many rare loss-of-function genetic diseases could be treated by inserting a copy of the functional gene in a genomic Safe Harbor Site or in the endogenous defective gene position under the control of the endogenous promoter, and development of such therapies would be unlocked by the ability to rapidly target recombinases to new sequences.”