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WAL0623 (Dynamin stabilizer)

A small molecule that stabilizes the enzyme dynamin, an ideal therapeutic target across a broad range of kidney diseases with a fundamental role in maintaining the structure, function, and health of podocytes and proximal tubule cells.

Dynamin is an enzyme that forms multimeric complexes that support the structural and functional integrity of both podocytes and proximal tubule cells. It does this by interacting with actin, myosin, and actin-binding proteins to facilitate actin cross-linking, strengthening the cytoskeleton, and regulating the shape, structure and stability of these specialized cells.

Podocytes actively maintain foot processes that form the slit diaphragm, a key part of the glomerular filtration barrier. Proximal tubule cells are cuboidal cells with a brush border made up of microvilli that are bathed in the lumen of the tubule. This brush border increases the surface area in contact with the tubular fluid enabling the active and passive transport of fluids and nutrients. Dynamin is a critical component to the morphology and function of both cell types.

In people with CKD, the structure and integrity of podocytes and proximal tubules are damaged, and kidney function declines as a result. Dynamin stabilizers have the potential to help reverse this damage by rebuilding the actin cytoskeleton and maintaining cellular morphology of podocytes and proximal tubule cells crucial to their function.9,10

 

  • 9 Soda, Keita, et al., JCI 122.12 (2012): 4401-44110
  • 10 Mukherjee, Kamalika, et al., Nature communications 13.1 (2022): 2422

Dynamin is responsible for the cytoskeletal integrity of podocytes

Healthy podocytes are strongly attached to the glomerular basement membrane (GBM) with interdigitating foot processes connected by the slit diaphragm. This forms a tight mesh to filter the blood and prevents proteins from leaking through. The cytoskeleton, made up of actin, plays a critical role by forming the frame within podocytes necessary for anchoring both the podocyte to the GBM and the slit diaphragm between foot processes.

At Walden, we have developed WAL0623, an oral small molecule dynamin stabilizer. Preclinical data show that WAL0623 directly targets the kidney, strengthens and restores the structure of podocytes and proximal tubules cells, and improves their viability and function. WAL0623 was efficacious in reducing proteinuria across several kidney disease models.

 

In vitro model of kidney injury demonstrates WAL0623 restores the
cytoskeleton (actin, orange) in podocytes.

WAL0623 is completing IND-enabling studies and will soon start first-in-human Phase 1 clinical studies.