Abstract: SA-OR63
Podocyte Gene Therapy Enables Glomerular Complement Modulation for IgAN Treatment
Session Information
- Glomerular Diseases: All about Podocytes
October 26, 2024 | Location: Room 1, Convention Center
Abstract Time: 05:50 PM - 06:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Cappelletto, Ambra, Purespring Therapeutics, London, United Kingdom
- Asfahani, Rowan Isabel, Purespring Therapeutics, London, United Kingdom
- Matthews, James, Purespring Therapeutics, London, United Kingdom
- Gennari, Alice, Purespring Therapeutics, London, United Kingdom
- Wood, Hannah L., Purespring Therapeutics, London, United Kingdom
- Illingworth, Sam, Purespring Therapeutics, London, United Kingdom
- Welsh, Gavin Iain, Purespring Therapeutics, London, United Kingdom
- Brown, Alice Claire, Purespring Therapeutics, London, United Kingdom
- Saleem, Moin A., Purespring Therapeutics, London, United Kingdom
Background
Adeno associated vector (AAV) gene therapy targeting the podocyte could pave the way to treat many glomerular diseases. We have recently shown successful podocyte targeting to rescue a genetic mutation. Here we present a novel AAV gene therapy candidate, PS-002, which targets podocytes enabling them to become ‘bio-factories’ secreting a complement regulator to specifically modulate complement activation in the glomerulus.
Methods
Efficacy of PS-002 was demonstrated using the grouped ddY mouse, a highly translationally relevant IgAN disease model. Safety and biodistribution of PS-002 were evaluated in Gottingen minipigs, a clinically translatable model for assessing dosing parameters via local infusion.
Results
The PS-002 candidate inhibited complement activation in grouped ddY mice as shown by reduced mesangial C3 deposits, and amelioration of disease phenotype by preservation of podocytes, reduction in mesangial expansion, inflammation and casts, and decreased proteinuria. In minipigs, we demonstrated successful gene expression across all kidney glomeruli at 28 days (100% glomeruli, n=3 pigs) and 56 days (99% glomeruli, n=3 pigs) post dosing, with a dose-response observed by RNAscope, qPCR and RT-qPCR. Low levels of AAV delivered protein were detected in the serum. These data demonstrate homogenous and sustained transduction of all kidney glomeruli using PS-002.
Toxicological assessments of renal and other organ function and post-study histopathological assessments revealed no treatment-related safety concerns and only low levels of transcript were detected in the liver, with no expression in the spleen or pancreas.
Conclusion
These data demonstrate (i) the feasibility of podocyte targeted gene therapy for glomerular specific modulation of complement, (ii) substantial non-clinical data to enable translation of PS-002 to clinical development for the treatment of IgAN, and (iii) the potential to use podocyte targeting AAV candidates to regulate complement activation in diseases beyond IgAN.