THE OFFICIAL NEWS SOURCE OF ACR CONVERGENCE 2022 • NOVEMBER 10-14



Single-cell science changing lupus nephritis outlook

Michelle Petri, MD, MPH
Michelle Petri, MD, MPH

Treatment for lupus nephritis lags far behind patient needs. The current treatment of choice, mycophenolate, produces a complete renal response in just half of patients treated for 12 months.

“That is completely unacceptable because patients who don’t respond are marching on toward dialysis, and we’ve just wasted an entire year on a treatment that didn’t help them,” said Michelle Petri, MD, MPH, Director of the Hopkins Lupus Center and Professor of Medicine at The Johns Hopkins University. “The way to do better is to apply cutting-edge science to lupus.”

Dr. Petri will describe some of that cutting edge science during Accelerating Medicines Partnership (AMP): Leveraging of Single Cell Tech for Insights into Lupus Nephritis from 2:30 – 3:30 pm Monday in Room A411-A412, Building A of the Georgia World Congress Center. The project explores gene expression in single kidney cells using RNA sequencing.

Jill P. Buyon, MD
Jill P. Buyon, MD

The largely exploratory phase one of the AMP lupus nephritis project identified a novel interferon pathway that might be targeted using biologics that have already been approved for indications in other diseases, Dr. Petri noted. Early work by Evan Der, PhD, and colleagues at Albert Einstein College of Medicine also found that patients who do not respond to mycophenolate after a year have activated fibrotic pathways.

“There are anti-fibrotic drugs under development and already approved for pulmonary fibrosis,” she said. “We want to borrow them for lupus nephritis.”

The project is moving into Phase II, focusing on kidney biopsy samples from a diverse population of about 200 lupus nephritis patients.

“Our patient cohort might be the most diverse set of patients, the most real-world set of patients, in any lupus nephritis study,” said Jill P. Buyon, MD, Director of Rheumatology at New York University School of Medicine. “We do not have very many non-Hispanic whites in this study. Our population is very heavily represented by the minority populations that are most heavily affected by lupus nephritis.”

Ilya Korsunsky, PhD
Ilya Korsunsky, PhD

The project will assess genetic differences among similar cell types across the cohort.

“We are coming up with new targets that go beyond what traditional histology can tell us,” Dr. Buyon said. “We now know that white cells talk to fibroblasts in the kidneys, and tubules talk to white cells. Some of this trafficking could lead us to receptors that can be identified as targets on a personal level.”

Analyzing the reams of data produced by single cell analysis is challenging. It’s not just the volume of data, said Ilya Korsunsky, PhD, Postdoctoral Fellow in Bioinformatics at Harvard Medical School. One of the toughest challenges is identifying and canceling the various sources of noise and technical variability inherent to single cell assays.

“If you sequence 5,000 cells from one donor and then sequence 5,000 cells from another donor and try to visualize the data in a naïve way, you’re going to run into trouble,” he warned. “The cells are going to group largely by donor rather than by cell type.

“What you really want to do is identify heterogeneity within each of these cell types that is common to multiple donors. We had to develop a specific algorithm, Harmony, to model biological and technical effects to identify shared cell types across different donors. Even if experiments were done with different technologies, we can still find common cell types. And we can scale to hundreds of thousands and millions of cells very easily with this algorithm.”

Dr. Petri is taking a different tack. Because serial kidney biopsies are impractical for most patients, she is focusing on urine proteomics as a liquid biopsy technique to track changes in disease over time. The goal is to identify urine proteins that track the genomic changes identified in kidney biopsies that correspond to specific clinical states.

Proteins excreted in the urine are routinely used to assess kidney function and kidney damage. A more refined analysis could very specifically assess the progression of lupus in the kidney. An easy and easily repeated liquid biopsy could also answer key questions such as whether a patient has proliferative or membranous disease, the precise source and degree of kidney damage, and why half of patients do not respond to mycophenolate.

“Rheumatology has lagged behind the kind of personalized medicine that is taken for granted in oncology,” Dr. Petri said. “AMP is basic research, but new findings are coming and they are being translated quickly. I expect to see clinical benefits within five years of the phase two results. This symposium shows the science of immunology becoming part of the treatment of our diseases.”