Master Protocol for a Phase I/II Open-label Safety and Efficacy Study of LNP.UCD.ABE, a Lipid Nanoparticle-delivered Base Editing Therapy, in Patients With Urea Cycle Disorders Due to Variants Amenable to Corrective Editing by LNP.UCD.ABE
This is a single-site Phase 1/2 open-label umbrella clinical trial designed to evaluate the safety, tolerability, and efficacy of a single intravenous dose of LNP.UCD.ABE in 5 pediatric subjects with severe infantile-onset UCDs. This is a master clinical protocol in which subjects with a variant in a urea cycle disorder (UCD) gene (CPS1, OTC, ASS1, ASL, ARG, NAGS, or SLC25A15) that is demonstrated to be amenable to corrective editing by an adenine base editor (ABE) would be eligible for enrollment.
• Diagnosis of a severe urea cycle disorder, in the judgement of the investigators.
• Molecular testing demonstrating homozygosity or compound heterozygosity for a disease-causing mutation in CPS1 that is targeted by a variant-specific version of the LNP.UCD.ABE drug product.
• Current or historical biochemical testing consistent with a urea cycle disorder
• At least one of the subject's alleles must be amenable to base editing by LNP.UCD.ABE, as assessed in vitro
• A history of an ammonia level of ≥400 μmol/L prior to age 12 months, unless a diagnosis was made prenatally and care was initiated immediately after birth
‣ If the patient is taking a nitrogen scavenger medication, their ammonia level may currently be in the normal range
⁃ If the patient is diagnosed prenatally, then personal history, family history, or analysis of mutations should indicate a high likelihood of a severe UCD.
• Subjects more than 8 weeks from the initial diagnosis of a UCD must have demonstrated:
‣ a persistent need for dietary protein restriction and chronic administration of a nitrogen scavenger medication, AND / OR
⁃ a recurrent hyperammonemic event AND / OR
⁃ a history of a hyperammonemia-induced seizure
• Weight \>3.5 kg at the time of screening
• Legal guardian(s) capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.