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
Rebecca Ahrens-Nicklas
Summary
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.
Description
Humans ingest protein to support growth and the synthesis of a number of key macromolecules. Nitrogen waste generated from protein catabolism is converted to ammonia, which under normal physiologic conditions is converted to urea via the urea cycle. Urea is then excreted in urine to maintain whole-body nitrogen homeostasis. Loss of function of any of the six enzymes of the urea cycle-encoded by CPS1 (carbamoyl phosphate synthetase 1), OTC (ornithine transcarbamylase), ASS1 (argininosuccinate synthetase), ASL (argininosuccinate lyase), ARG (arginase), and NAGS (N-acetylglutamate synthetase)-res…
Eligibility
- Age range
- 24–5 years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: 1. Diagnosis of a severe urea cycle disorder, in the judgement of the investigators; 2. Molecular testing demonstrating homozygosity or compound heterozygosity for a disease-causing mutation in a urea cycle disorder gene (CPS1, OTC, ASS1, ASL, ARG, NAGS, or SLC25A15) that is targeted by a variant-specific version LNP.UCD.ABE; 3. Current or historical biochemical testing consistent with a urea cycle disorder; 4. At least one of the subject's alleles must be amenable to base editing by LNP.UCD.ABE, as assessed in vitro; 5. A history of an ammonia level of ≥400 μmol/L prior t…
Interventions
- BiologicalLNP.UCD.ABE
Each subject will have a personalized variant-specific LNP.UCD.ABE developed and evaluated in real time. Each member of the LNP.UCD.ABE drug product (DP) family is a lipid nanoparticle (LNP)-based editing therapeutic comprising lipid excipients, a messenger RNA (mRNA) drug substance (DS) encoding an adenine base editor (ABE), and a single guide RNA (gRNA) DS.
Location
- Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania