Cell-Based Potency Assay For OTC Deficiency Therapy

Revolutionizing the Treatment of Urea Cycle Disorders

A Targeted Approach Using ECUR-506 and Cell-Based Potency Assays

Neonatal ornithine transcarbamylase (OTC) deficiency, the most common and severe urea cycle disorder, presents with life-threatening hyperammonemia in newborns. Left untreated, it leads to devastating neurological damage and mortality. Conventional treatment options are limited, with liver transplantation as the only curative intervention for severe cases.

ECUR-506 is a cutting-edge gene editing therapy using a dual-vector AAV (adeno-associated virus) approach. ECUR-506A introduces the ARCUS® nuclease targeting the PCSK9 locus, while ECUR-506D carries the functional OTC transgene designed for site-specific genome integration.

To evaluate the therapeutic effectiveness of ECUR-506, Pharmaron and iECURE have developed two complementary cell-based potency assays:

A PCR/qPCR assay confirms precise integration of the OTC transgene at the intended genomic locus (PCSK9).
A functional enzyme assay quantifies OTC activity via LC-MS/MS by measuring the formation of citrulline from labeled ornithine.

Functional Validation and Technical Findings

In vitro studies using Huh7 cells co-transduced with ECUR-506A and ECUR-506D showed:

Successful genomic integration of the OTC gene, validated by Sanger sequencing.
A dose-dependent increase in OTC enzymatic activity, demonstrating functional correction of the metabolic defect.
Quantification of enzyme kinetics using LC-MS/MS confirmed citrulline production rates that correlate with vector dosage.

These findings underscore the potential of in vitro potency assays to establish the functional reliability of gene therapy candidates targeting rare metabolic disorders, such as OTC deficiency.

Download the Full Poster Presentation

Discover more about the design and performance of our potency assays and how they contribute to the preclinical validation of gene therapies.

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