by Erica Yirenkyi, Iva Toudjarska, University of Connecticut

Graphical abstract. Credit: Molecular Therapy (2024). DOI: 10.1016/j.ymthe.2024.10.020

Since its discovery in 1998 and winning the Nobel Prize in 2006, ribonucleic acid (RNA) interference has become an invaluable tool for drugmakers to silence disease-causing genes. Nearly three decades later, drug makers have developed six approved small interfering RNA (siRNA) therapeutics in the therapeutic areas of neurology, cardiovascular, endocrine, and metabolism, such as amyloidosis, familial amyloid polyneuropathies (FAPs), hyperlipidemia and other diseases.

Delivery of siRNA therapeutics to a variety of tissues and cells of interest has remained a major challenge for the application of siRNA therapeutics in humans. The current state of the art is N-acetylgalactosamine siRNA conjugates (GalNAc-siRNA), which deliver exclusively to the liver, limiting the number of diseases that can be treated.

Developing RNA conjugational approaches for targeting extra-hepatic tissues is the ultimate goal for RNA therapeutics delivery.

In a recent Molecular Therapy publication by Vikas Kumar and colleagues titled "Efficient and selective kidney targeting by chemically modified carbohydrate conjugates," Raman Bahal's team at UConn School of Pharmacy Department of Pharmaceutical demonstrates the development of a novel kidney-targeted delivery platform called RENTAC-Renal Tubule Targeting Carbohydrate.

RENTAC targets the kidney via the megalin receptor family—an endogenous cell-surface receptor family expressed at high levels on the apical side of proximal tubule epithelial cells (PTECs), resulting in the internalization of the conjugated molecules.

The team has demonstrated efficient enrichment of synthetic RNA molecules and small molecules in the kidney, and that platform may be useful for treating conditions like kidney fibrosis. Bahal's team actively collaborated with Stefan Somlo, a C. N. H. Long Professor of Medicine (Nephrology) and Professor of Genetics at Yale, to confirm that RENTAC targets PTEC in vivo.

When asked about his lab work, Bahal remarked, "The kidney, and associated diseases, are an area to which the industry pays a lot of attention, but not many effective delivery systems are available in the clinic right now. We developed a novel carbohydrate chemistry-based conjugate that can deliver RNA therapeutics and even small molecules to the kidney."

"The opportunities for genetic medicine application to kidney diseases are growing," says Somlo. "One of the barriers to translational progress is the limited ability to target therapies for increased delivery to kidney tissue.

"The collaboration between our group at Yale and Bahal's group at UConn brings together our expertise in the discovery of treatment targets with Bahal's unique discovery of how to deliver drugs to the kidney. The synergies in our work together really offer an exciting opportunity to develop a paradigm for how to design and deliver new treatments to kidney disease patients."

More information: Vikas Kumar et al, Efficient and selective kidney targeting by chemically modified carbohydrate conjugates, Molecular Therapy (2024). DOI: 10.1016/j.ymthe.2024.10.020

Journal information: Molecular Therapy 

Provided by University of Connecticut