Regenxbio Inc. (Nasdaq: RGNX) announced that the US FDA placed clinical holds on two investigational gene therapy programs targeting ultra-rare mucopolysaccharidosis (MPS) disorders, after the recent identification of a central nervous system (CNS) neoplasm in a pediatric participant. The regulatory action affects RGX-111 for MPS I (Hurler syndrome) and RGX-121 for MPS II (Hunter syndrome), underscoring evolving safety scrutiny in the rapidly advancing gene therapy field.

As per Regenxbio’s notice, the clinical holds follow detection of an intraventricular CNS tumor during routine imaging of a five-year-old child treated with RGX-111 four years earlier. Preliminary genetic analysis of the resected tumor identified an adeno-associated virus (AAV) vector genome integration event near the proto-oncogene PLAG1, raising concerns about possible insertion-related oncogenic activation, albeit causality has not been established. The affected participant remains asymptomatic with positive developmental progress to date.

Because of product and patient population similarities between the two programs, the FDA extended the hold to RGX-121 while continuing its investigation. Regenxbio noted that there was no evidence of neoplasm reported in the nine other participants treated with RGX-111 nor in the 32 participants treated with RGX-121. CEO Curran Simpson expressed surprise that the clinical hold had been extended to both programs, noting “These are separate therapies, and the positive safety profile of RGX-121 in more than 30 patients treated, including those dosed nearly seven years ago, remains unchanged”.

Regenxbio and its partners will now work with the FDA to resolve outstanding safety questions and determine conditions for lifting the holds, as the company continues advancing its broader pipeline of AAV-based therapies for rare and retinal diseases.

About RGX-111 and RGX-121

Both candidates leverage AAV-mediated gene delivery to target the central nervous system, addressing the profound unmet need for therapies that can cross the blood-brain barrier and correct enzyme deficiencies driving neurological decline in MPS disorders:

RGX-111 uses an AAV9 vector to deliver the IDUA gene, aiming to restore alpha-L-iduronidase activity in the brains of patients with MPS I, a lysosomal storage disorder characterized by glycosaminoglycan accumulation and progressive neurocognitive impairment.

RGX-121 delivers the IDS gene to restore iduronate-2-sulfatase activity in MPS II, an X-linked condition that similarly causes buildup of heparan sulfate in tissues including the CNS. This one-time therapy has shown biomarker and neurodevelopmental improvements in pivotal studies and was under FDA review with a PDUFA date expected in early February 2026 prior to the hold.

Both programs had earned regulatory incentives such as Orphan Drug and Rare Pediatric Disease designations in recognition of their potential to address devastating pediatric diseases with no effective CNS-targeted therapies.

Research context

AAV vectors have become the workhorse of systemic and CNS gene therapy due to their low immunogenicity and ability to mediate long-term gene expression in non-dividing cells. However, vector integration events, while rare compared with integrating vectors like retroviruses, remain a theoretical safety concern as they can disrupt host genomes or dysregulate nearby oncogenes, with risks heightened in developing tissues of pediatric patients.

There have been a series of high-profile FDA clinical holds for genetic therapy developers, from preclinical to Phase III stage, triggered by severe safety concerns including acute hepatotoxicity, immunogenicity, insertional mutagenesis leading to potential cancer risk, and other organ toxicities. Sarepta Therapeutics last year faced delay to two Phase III trials for its Duchenne muscular dystrophy hope Elevidys (SRP-9001) over liver toxicity concerns, while other companies impacted by holds include BioMarin, uniQure, and Solid Biosciences.