Study of LNP.UCD.ABE in Patients With Urea Cycle Disorders

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 CPS1 that is targeted by a variant-specific version of the LNP.UCD.ABE drug product.
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 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.

6. 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
7. Weight >3.5 kg at the time of screening
8. 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.

Exclusion Criteria:

1. Abnormal liver function, electrolyte, coagulation, or blood count laboratory values thought not attributable to the underlying urea cycle disorder;
2. Demonstrated need for urgent liver transplantation due to liver failure, in the opinion of the investigators;
3. Participation in a prior gene therapy trial or participation in a trial of an investigational product in the last 12 months;
4. History of liver transplantation;
5. Any other diseases or conditions that the investigators would consider to pose unacceptable risk to the subject;
6. Inability or unwillingness to comply with the visit schedule and study assessments;
7. Any genetic variation in the causative urea cycle disorder gene that, in the opinion of the investigators, may decrease the potential efficacy of the drug product;
8. History of severe hypersensitivity or anaphylaxis to polyethylene glycol (PEG)-containing products, such as PEG-containing vaccines or laxatives