Abstract: SA-OR061
Glomthera Platform Enables Durable COL4A5 Expression for the Treatment of X-Linked Alport Syndrome
Session Information
- Glomerular Diseases: Therapeutic Strategies Emerging from Basic Research
October 24, 2026 | Location: Mile High Ballroom 4D, Convention Center
Abstract Time: 05:20 PM - 05:30 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Smith-Moore, Sarah, Purespring Therapeutics Limited, London, England, United Kingdom
- Gurung, Kritima, Purespring Therapeutics Limited, London, England, United Kingdom
- Cappelletto, Ambra, Purespring Therapeutics Limited, London, England, United Kingdom
- Illingworth, Sam, Purespring Therapeutics Limited, London, England, United Kingdom
- Brown, Alice Claire, Purespring Therapeutics Limited, London, England, United Kingdom
Background
The opportunity to treat X-linked Alport syndrome (XLAS) by restoring healthy COL4A5 expression in the glomerular basement membrane (GBM) using gene therapy has been hampered by delivery challenges to podocytes and the large size of the COL4A5 sequence. Using our podocyte-targeting Glomthera® platform, which is already in clinical development for the treatment of IgAN, we present how we overcame these challenges through development of a novel dual AAV gene therapy candidate, PS-003, that delivers full-length COL4A5 for the treatment of XLAS.
Methods
Functionality of PS-003 and a PS-003 murine surrogate was demonstrated using in vitro studies in human podocytes and in the widely used G5X mouse model for XLAS, respectively.
Safety and biodistribution of a human PS-003 surrogate vector was evaluated in Gottingen minipigs, a clinically translatable model for assessing dosing parameters and toxicology via the intended clinical route of administration.
Results
In vitro studies in human podocytes demonstrated robust production of functional COL4A5 protein capable of efficient COL4α3α4α5 heterotrimer formation and secretion.
A murine analogue of PS-003 led to consistent and homogenous expression of COL4A5 in the glomeruli of treated mice, as demonstrated by immunofluorescence and mass spectrometry. COL4A3 and COL4A4 proteins were stabilised, demonstrating in vivo functionality of PS-003 dual vector technology.
In minipigs, successful vector delivery and reconstitution of the full length COL4A5 gene was demonstrated in kidney by qPCR and multiplexed ddPCR. Gene expression was also confirmed by RT-qPCR and Basescope.
Toxicological assessments of renal and other organ function and post-study histopathological assessments revealed no treatment-related safety concerns in any dosed animals, and only low levels of transcript were detected in the liver, spleen, and pancreas.
Conclusion
These data demonstrate (i) the feasibility of using a podocyte-targeted dual AAV approach to restore full-length COL4A5, (ii) the preclinical rationale for the progression of PS-003to clinical development for XLAS, and (iii) the potential to use a similar approach to address COL4A3- and COL4A4-deficient Alport Syndrome.