Insilico Medicine and MIKADO team up to find new treatments for cystinosis

A team led by researchers at the Mechanisms of Inherited Kidney Disorders (MIKADO) group at the University of Zurich (Zurich, Switzerland) has used Insilico Medicine's generative artificial intelligence (AI) target discovery engine, PandaOmics, to identify actionable drug targets for the lysosomal storage disease cystinosis and to validate them in preclinical models of the disease. These results, which open new therapeutic possibilities for this devastating disease, were published June 14 in the journal Nature Communications. Collaborators include scientists from Microsoft Research-University of Trento Centre for Computational and Systems Biology in Italy, the Cystinosis Research Foundation (Irvine, CA) and the Program Innovative Therapies in Rare Diseases (ITINERARE) in Zurich.

Cystinosis is a rare genetic disease characterized by inappropriate storage of the amino acid cystine in cells, posing a lifelong threat to the body of those affected. Nephropathic cystinosis stands as the most common and severe form of the disease, typically emerging in infancy. The relentless accumulation of cystine slowly destroys the body's organs, causing kidney failure, diabetes, hypothyroidism, myopathy, and central nervous system deterioration. There are currently no curative treatments for children with cystinosis.

Amino acid transporters play a vital role in facilitating the movement of essential nutrients across the membrane of lysosomes, specialized vesicles that play an essential role in handling nutrients and regulating cellular metabolism. Cystinosis is caused by mutations that invalidate the cystinosin (CTNS) transporter, causing cystine to accumulate, and driving lysosomal storage disease that damages multiple organs, including the kidneys. Scientists suspected that the mechanism responsible for the cell damage was connected to the regulation of rapamycin complex 1 (or mTORC1), an evolutionary conserved protein controlling cell growth and geroprotective signaling pathways that promote healthy longevity.

In the study, the researchers used the PandaOmics platform as a novel way to prioritize disease-target associations and prioritize actionable (drug) targets in cystinosis cells. The AI-based analysis predicted that mTOR leads a ranked list of actionable drug targets. The researchers then extended these unbiased approaches by cross-species validation in preclinical models of cystinosis and mechanistic in vitro studies in cellular systems. These findings indicate that hyperactive mTOR signaling drives the dysfunction of kidney tubular cells and is a targetable pathway in cystinosis, so the researchers conducted experiments to confirm its therapeutic effectiveness. Tested on cellular systems and animal models, such as rat and zebrafish, the researchers found that treatment with the Food and Drug Administration (FDA)-approved therapeutic rapamycin restores the degradative activities of the lysosomes and ameliorates the dysfunction of kidney tubular cells – the earliest telltale manifestation of the disease. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.

We are very pleased to have the first findings emerge from this important collaboration. Our AI platform has provided new insights into cellular and molecular pathways that drive life-threatening complications in cystinosis that we hope will ultimately lead to new treatment options for cystinosis patients."

Alex Zhavoronkov, Ph.D. Insilico Medicine Founder and CEO

The research collaboration between Insilico and MIKADO was first announced in March 2022.

"Cystinosis is a commonly neglected disease with a large unmet need. With the power of artificial intelligence-driven, systems biology-based drug discovery, we have unlocked new understanding of cystinosis disease and accelerated the discovery of actionable drug targets, with the goal of bringing novel breakthrough medicines to patients," said Professor Olivier Devuyst, MD, head of MIKADO group at the UZH.

"Ultimately, we want to improve the quality of life for those affected by the disease and bring tangible hope to thousands of cystinosis patients around the world," said Dr. Alessandro Luciani, principal scientist and team leader at MIKADO at UZH.