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

ConditionsUrea Cycle Disorders Carbamoyl-Phosphate Synthase I Deficiency

Trial statusRecruiting

Trial phasePhase 1, Phase 2

Trial typeInterventional

Biological sexAll

Age24-5

SponsorRebecca Ahrens-Nicklas

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

Abnormal liver function, electrolyte, coagulation, or blood count laboratory values thought not attributable to the underlying urea cycle disorder;

Demonstrated need for urgent liver transplantation due to liver failure, in the opinion of the investigators;

Participation in a prior gene therapy trial or participation in a trial of an investigational product in the last 12 months;

History of liver transplantation;

Trial design

Design model

Single group

Treatments tested in this trial

LNP.UCD.ABE
Biological/Vaccine
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.

Treatment groups

7 Participants

are divided into 1 treatment group

Group A: ExperimentalExperimental treatment 1 intervention

Trial outcomes

Primary outcomes

Safety and tolerability of a single intravenous dose of LNP.UCD.ABE

Incidence of treatment-emergent adverse events as assessed by CTCAE version 6.0 criteria at 52 weeks after LNP.UCD.ABE administration.

Time frame

52 weeks

Secondary outcomes

Clinical efficacy of a single intravenous dose of LNP.UCD.ABE

The proportion of the population that can tolerate: 1. an increase in protein intake to 100% of the recommended dietary allowance (RDA) for age and/or at least a 50% reduction in the nitrogen scavenger medication dose, without an associated hyperammonemic event \[defined as an ammonia level ≥ 2.5× upper limit of normal (ULN) on a non-hemolyzed specimen and the presence of symptoms of hyperammonemia\], by 16 weeks after administration of LNP.UCD.ABE.

Time frame

16 weeks

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Rebecca Ahrens-Nicklas

Lead sponsor

Children's Hospital of Philadelphia

Sponsor institution

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Advanced Research Projects Agency for Health (ARPA-H)