Nonprofit OTXL In-Licenses First Gene Therapy, OTXL-101, for Rare OTCD

The Orphan Therapeutics Accelerator (OTXL) has in-licensed its first therapy: OTXL-101, a liver-targeted AAV gene therapy for ornithine transcarbamylase deficiency (OTCD), acquired from UCL Ventures, University College London's commercialization company, and the Children's Medical Research Institute (CMRI). The candidate, previously named AAVLK03hOTC, was developed by Paul Gissen, MBChB, PhD, and his UCL OTCD project team together with Ian Alexander, MBBS, PhD, and his group at CMRI.

The deal marks the first asset into OTXL, a nonprofit biotech built to use tax and other incentives to, in CEO and co-founder Craig Martin's words, "liberate and reininitiate development of shelved therapies for rare and ultra rare conditions." Martin told GEN the team screened more than 80 therapeutic programs before settling on this one. "We first started looking at it almost two years ago," he said.

Why was the therapy shelved?

OTXL-101 was originally outlicensed to Bloomsbury Genetic Therapies, which launched a Phase I/II study called HORACE — Halting Ornithine transcarbamylase deficiency with Recombinant AAV in Children. The first patient, a 10-year-old male with late-onset OTCD, was dosed at Great Ormond Street Hospital in December 2023. The trial was designed for 12 patients. When Bloomsbury shut down in 2025, the program went back to UCL and CMRI.

OTXL had moved on to other candidates, but the collapse prompted a rethink. "We started negotiating with them and found everybody was really feeling like this was a therapy that needed to get to patients. And we were able to structure the deal in such a way that it really fit our model and provided a more viable path forward for the therapy," Martin said.

What does the clinical evidence show?

Preliminary results from the first patient were presented at the 2025 ASGCT annual meeting. Clinical evidence now spans more than two and a half years and, according to Martin, "gives us a sense of its potential to benefit patients." The treated patient came off Ravicti, a nitrogen-scavenging medicine for chronic ammonia control, and off a restricted protein diet, and has continued to do well. That's a single-patient data set — projections beyond it should be treated with care.

OTCD itself is caused by OTC gene mutations that cut ornithine transcarbamylase activity, breaking the liver's urea cycle and letting toxic ammonia accumulate. Episodes can trigger brain injury and coma. Current management — protein restriction, nitrogen scavengers, amino acid supplements — leaves patients at risk; liver transplantation restores metabolic control but demands lifelong immunosuppression. Orphanet estimates birth frequency at roughly one in 56,500 to one in 113,000 live births.

OTXL-101 carries U.S. and EU orphan drug designations plus a U.S. rare pediatric disease designation. It targets children and adolescents.

How does the OTXL model work?

OTXL is one prong of a four-part infrastructure for rescuing shelved cell and gene therapies:

• OTXL, the nonprofit that in-licenses and develops programs.
• Orphan ClinDevNet, a network of CDMOs, CROs and other partners working under reduced-cost, success-based agreements.
• Orphan Therapies, the commercial subsidiary set up a year ago, which recently established commercial availability of an ex vivo cell therapy for Wiskott-Aldrich syndrome. Approved products can also be outlicensed.
• CGTxchange, an AI-enabled marketplace, diligence and deal-making platform created through a joint venture with the American Society of Gene & Cell Therapy (ASGCT). OTXL-101 was initially identified using the platform that now underpins it.

What comes next?

Near-term work on OTXL-101 is concrete: stability and potency testing on material already manufactured for the HORACE trial, and patent extensions in multiple countries to secure broad access. The therapy will be listed on CGTxchange. "We have some of the funds required to continue to move it forward, but we'd like to be able to have a set of funding that would allow us to extend ideally past the next inflection point," Martin said.

OTXL's screening criteria for future deals hinge on unmet need and clinical evidence, whatever the stage: "is this an area of high unmet medical need? Is it a therapeutic approach that we have a good understanding of and based on evidence from clinical trials, wherever they are in that process?" Martin said the group is modality-agnostic and in active conversations on clinical-stage and commercial-stage candidates alike — including products where "the traditional commercial model just doesn't work for big biotechs or biopharma companies."