Eli Lilly plans to expand its hearing loss therapy pipeline by collaborating with Seamless Therapeutics to apply the company’s next-generation gene-editing approach, based on programmable recombinases, to develop and commercialize hearing loss treatments—a deal that could generate more than $1.12 billion for the German startup.
Under a strategic global research collaboration and licensing agreement with Lilly, Seamless has agreed to design and program site-specific recombinases directed toward correcting mutations in undisclosed genes of interest related to hearing loss. Seamless has agreed to grant Lilly an exclusive license to the programmed recombinases to advance through preclinical and clinical drug development and commercialization.
Lilly and Seamless will develop the treatments based on Seamless’s recombinase platform, which is designed to perform large, precise insertions of DNA in any target gene sequence, independent of the cell’s natural DNA repair pathway.
Seamless will use its platform to identify a programmable recombinase capable of inserting Lilly’s genes of interest.
“We’ll use a series of different models and bioinformatics to scan all the nucleotides in the region that they’re interested in. We’ll identify areas in there that are similar to, say, the wild-type binding site of these enzymes, or that we have optimism that we can evolve it to those particular sites,” Albert Seymour, PhD, Seamless’s president, CEO, and managing director, told GEN.
Seamless uses its platform to reprogram two recombinase families: Cre (short for causes recombination) and large serine recombinases.
“We’ll start in a region of the genome. We’ll pick nucleotide sequences in there, and then we evolve the enzymes specifically for activity at those particular sites,” Seymour said. “We evolve in bacteria, because they’re very fast, we can do a lot of cycles really quickly, and then we take those enzymes and then test in mammalian cell lines.”
TU Dresden spinout
Seamless is a Technische Universität Dresden (TU Dresden) spinout founded to commercialize the recombinase reprogramming discoveries of its scientific founders—Prof. Dr. rer. nat. Frank Buchholz, PhD, professor for medical systems biology and head of translational research at TU Dresden’s university cancer center, and Felix Lansing, PhD, co-founder and CTO of Seamless. Buchholz, who chairs Seamless’s Scientific Advisory Board, and his research team discovered they can use reprogrammed recombinases using directed evolution.
“They can take that enzyme and randomly mutate it and screen it and cycle it until you keep the properties that we all like about the recombinases, which are these seamless edits, but have it change its binding site. And you can change its binding site at the DNA level to sites that you want in the genome,” Seymour explained. “Seamless has taken that academic process, which used to take two years in order to find an enzyme, and really shortened it down to more industrial industry standards, which would be maybe six months.”
Seamless’s editing approach drew interest from Lilly, given its commitment in recent years to expand in genetic medicines. The pharma giant launched the $700 million Institute for Genetic Medicine in 2021 in Boston’s Fort Point section as part of a strategy of advancing gene and gene editing therapies, RNA- and other nucleic acid-based therapeutics. The Institute operates in Boston and New York City, where Lilly-owned neuroscience gene therapy developer Prevail Therapeutics is based. Prevail was acquired in 2021 for up to $1.04 billion.
The Lilly-Seamless collaboration is the culmination of talks begun in 2024 when a team from Lilly approached Seamless seeking to learn more about its recombinase technology.
“There was some recognition and knowledge of what Frank and his team were doing. So, Lilly came to us about the technology initially. And then through a series of discussions, showing them what progress we had been making, that’s when we got together and said, hey, maybe this could really be applied to a gene of interest that Lily was interested in,” Seymour recalled.
“We look at it as a great partnership for Seamless, because it gets us into a disease area that we were not working on, and allows us to bring the expertise in the recombinase discovery and the editing part. Lilly brings the expertise of the disease biology, the IND enabling, as well as the development and commercialization in these fields,” Seymour added. “It’s a win-win, if you will, putting the two companies together.”
Expanding hearing loss pipeline
The Lilly collaboration—Seamless’s first announced partnership with a biopharma giant—expands the portion of Lilly’s pipeline focused on hearing loss. That portion is anchored by AK-OTOF, a gene therapy designed to treat sensorineural hearing loss due to mutations in the otoferlin gene (OTOF). AK-OTOF was initially developed by Akouos, which became a subsidiary of Lilly after it acquired the hearing loss therapy developer in 2022 for up to $610 million.
Two years later, Lilly announced positive initial clinical results from the Phase I/II AK-OTOF-101 trial (NCT05821959) showing AK-OTOF to have restored hearing within 30 days of dosing in the trial’s first participant, a person said to have a decade-plus history of profound hearing loss.
AK-OTOF is one of several gene therapies in clinical-phase development for hearing loss indications. Others include Regeneron Pharmaceuticals’ DB-OTO, a dual adeno-associated virus (AAV) gene therapy designed to treat children with profound, congenital hearing loss caused by mutations in the OTOF gene; and Sensorion Therapeutics’s OTOF-GT (SENS-501), a dual AAV gene therapy being developed to treat profound congenital deafness caused by otoferlin deficiency.
Akouos’ pipeline also includes another clinical phase gene therapy candidate—AAVAnc80-antiVEGF (also called AK-antiVEGF), an AAV-based treatment for vestibular schwannoma (also called acoustic neuroma) that targets vascular endothelial growth factor and uses the synthetic Anc80 capsid. The treatment is being assessed in the Phase I portion of a Phase I/II trial (NCT06517888) that has an estimated primary completion date of August 2029.
Beyond AAVAnc80-antiVEGF, Akouos’ pipeline, according to its website, includes preclinical programs designed to treat Usher syndrome type 3A by targeting CLRN1, GJB2-mediated hearing loss by targeting GJB2, and programs designed to treat autosomal dominant hearing loss and promote hair cell regeneration.
Lilly also expanded its footprint into treatments for sensorineural hearing loss last year by launching a collaboration with Rznomics to develop therapies based on the South Korean biopharma’s RNA-editing trans-splicing ribozyme platform technology. The collaboration could generate up to $1.3 billion for RZnomics, not counting royalties on product sales.
The collaboration with Lilly adds hearing loss to the as-yet-undisclosed internal therapeutic areas of focus for Seamless. The company’s goals for 2026 include identifying its first development candidate from its internal pipeline.
Seamless formally launched in 2023 with €12.5 million ($14.8 million) in seed financing co-led by Forbion and Wellington Partners, with nondilutive funding from Germany’s Federal Ministry of Education and Research (BMBF) through its GO-Bio initiative aimed at supporting innovative life sciences startups.
$40M in seed funding
That seed financing grew later that year to $25 million, then to $40 million, not including the upfront payment it will receive from Lilly, the amount of which is not being disclosed. Seamless also attracted two additional investors, 4Beyond and UCB Ventures, the venture capital arm of UCB.
In addition to the upfront cash, Lilly has agreed to pay Seamless funding committed to research and development, plus payments tied to achieving development and commercial milestones—all totaling more than $1.12 billion. That sum does not include tiered royalties on any successfully marketed drugs developed through the collaboration.
Seamless is based in Dresden, Germany, with offices in Lexington, MA, which are expected to grow as the company moves into development phases for its treatment candidates. Dresden is where Seamless carries out its directed evolution process for recombinase discovery, since many of its researchers emerged from Dresden University, from which Seamless licenses its technology. In Lexington, Seamless is building out R&D expertise to take its recombinases from pharmacology, disease biology, and other IND-enabling studies through clinical and regulatory development.
Lexington is a suburb within the Boston/Cambridge, MA, region—the nation’s leading cluster in GEN’s A-List of Top 10 U.S. Bioppharma Clusters. Seamless’ desire to tap into Boston-area expertise brought the company to Seymour’s attention in November 2023.
Three months later, he joined Seamless as its CEO after previously serving as CSO and later president and CEO of Homology Medicines, a rare disease genetic medicine developer that merged in 2024 with Q32 Bio. Earlier, Seymour served in senior leadership positions at Shire and Pfizer.
“The company really resonated with me because they were working on some enzymes that I knew a little bit about and was familiar with,” Seymour said. “I liked the idea that these are enzymes that have been around for a long time, so there was quite a bit known about them. I just felt it was a very differentiated approach to gene editing, and I had some of that experience.”
