Podocyte Gene Therapy Seems Promising for IgAN in Preclinical Research

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Podocyte targeted gene therapy for the intended treatment of IgA nephropathy (IgAN) seems to be feasible, according to new preclinical animal data from Purespring Therapeutics on its candidate PS-002.

The data were presented at the American Society of Nephrology’s Kidney Week 2024, held in San Diego, California on October 23-26, by Ambra Cappelletto, PhD, a principal scientist at Purespring.

“It used to be thought that patients with IgANhave a really slowly progressing disease, and yeah, give them some renin-angiotensin-system inhibitors and come back in 3 years. But now that there's been more research... [that makes]it pretty clear that patients with some proteinuria, they have a much more rapid progression than people thought in the past, Fredrik Erlandsson, MD, PhD, chief medical officer, Purespring Therapeutics, told HCPLive®.

Cappelletto presented data demonstrating PS-002's efficacy in an IgAN mouse model, in which the therapy inhibited complement activation as shown by reduced mesangial C3 deposits. PS-002 also preserved podocytes; reduced mesangial expansion, inflammation, and casts; and decreased proteinuria, suggesting an improved disease phenotype.

“I think we were quite positively surprised to see how good our delivery of our gene therapy was... The data that we produced are strongly saying that we have efficacy with our gene therapy... When we moved to the to the pig [model] the transduction efficiency is what really surprised us, and it's what is actually making a difference,” Cappelletto told HCPLive during the meeting.

In Gottingen minipig models, the investigators achieved 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. They used RNAscope, qPCR and RT-qPCR to observe dose response and detected low levels of AAV delivered protein in the serum.

Cappelletto and colleagues found no treatment-related safety concerns when conducting toxicological assessments of renal and other organ function and post-study histopathological assessments. While low levels of transcript were detected in the liver, no expression was detected in the spleen or pancreas.

“Initially, gene therapy will probably for a select group of patients that are not sufficiently managed by current standards and even new standards of care that will arrive in the future, I think that there will always be a group of patients [whose] proteinuria doesn't come down low enough for them to have an acceptable risk for renal replacement therapy within their lifetime, that population will always exist, even with new therapies that we're seeing right now. So [there] will always be a group of patients that need further therapy,” Erlandsson said.

REFERENCE

Cappelletto A, Asfahani RI, Matthews J, et al. Podocyte Gene Therapy Enables Glomerular Complement Modulation for IgAN Treatment. Presented at: ASN Kidney Week 2024. San Diego, CA. October 23-27, 2024. Abstract: SA-OR101