Abstract: FR-PO0114
ONYX-101: Development of a Kidney-Targeted Dual-Vector Adeno-Associated Virus Gene Therapy Candidate for X-Linked Alport Syndrome Using NYX Capsids
Session Information
- Hereditary Glomerular and Tubulointerstitial Kidney Diseases
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Main, Nathan M., NIONYX BIO, New York, New York, United States
- Perin, Laura, Children's Hospital Los Angeles, Los Angeles, California, United States
- Da Sacco, Stefano, Children's Hospital Los Angeles, Los Angeles, California, United States
- Tyrpien, Magdalena, NIONYX BIO, New York, New York, United States
- Lisowski, Leszek, NIONYX BIO, New York, New York, United States
- Ruiz, Juan, NIONYX BIO, New York, New York, United States
Background
X-linked Alport syndrome is a progressive inherited kidney disease caused by pathogenic variants in COL4A5, resulting in defective type IV collagen assembly and glomerular basement membrane dysfunction. Affected patients typically develop hematuria early in life, followed by proteinuria, declining kidney function, and progression to end-stage kidney disease (ESKD), often during adolescence or early adulthood in males. There are no approved disease-modifying therapies that restore COL4A5 function or address the underlying genetic defect. While adeno-associated virus (AAV)-mediated gene transfer offers the potential for a durable therapeutic approach, kidney gene therapy remains limited by inefficient renal delivery, challenges in glomerular cell targeting, off-target transduction, and AAV payload constraints associated with COL4A5 gene size. ONYX-101 is a kidney-targeted gene therapy program designed to enable durable COL4A5 restoration through dual-vector AAV delivery using NYX capsids optimized for renal cell targeting
Methods
Multiple therapeutic constructs compatible with full-length COL4A5 reconstitution at the DNA, RNA, and protein levels were designed and evaluated using orthogonal molecular and functional assays. These studies aimed to identify configurations compatible with dual-vector packaging, reconstitution efficiency, and robust expression. Candidate constructs were assessed in vitro using different cell lines, including patient-derived podocytes from individuals with Alport Syndrome.
Results
A lead therapeutic configuration utilizing an RNA-trans splicing strategy demonstrated robust expression of full-length COL4A5 at both the RNA and protein levels and was advanced for further evaluation. PODO/TERT256 cell transduction confirmed podocyte expression of human COL4A5 protein following dual-vector ONYX-101 delivery. Additional validation was performed in amniotic-derived normal and Alport Syndrome human podocytes, supporting effective reconstitution of COL4A5 from dual AAV vectors. Ongoing studies include functional evaluation of ONYX-101 in the Glomerulus-On-A-Chip model set up with AS-derived podocytes and in vivo efficacy evaluation of ONYX-101 in the G5X Alport mouse model.
Conclusion
Collectively, these data support ONYX-101 as a kidney-targeted dual-vector AAV gene therapy candidate for X-linked Alport Syndrome.