Scientific Approach

Drug Discovery Engine to improve neuronal health

Clearance of toxic cellular components, whether they are damaged organelles, aggregated proteins, or accumulated lipids, is a fundamental function required for cell health. Mutations that impair clearance pathways are associated with the cause of multiple neurodegenerative diseases, including those with cognitive dysfunction. Caraway’s targeted approaches combine genetic data and unique biological understanding to discover small molecules that activate neurons’ clean-up and recycling processes thereby accelerating clearance of toxic materials and defective cellular components.

Leveraging patient data

Patient genomic data highlight the critical importance of lysosomal clearance pathways in maintaining healthy neurons.

Modeling diseased human neurons

One of the challenges facing drug discovery is accurately modeling human diseases in vitro. At Caraway, we overcome this difficulty by utilizing patient-derived induced pluripotent stem cells (iPSCs). These cells can be stimulated to form neurons in the laboratory so that we can recreate aspects of disease and observe how drugs work on them. The cell models allow us to quickly test potential drug molecules for their ability to enhance clearance of toxic accumulations in the cells of interest.

TRPML1 Modulators

TRPML1 is a member of the Transient Receptor Potential ion channel superfamily. The channel is targeted primarily to lysosomes, which serve as the recycling centers within a cell. Cellular components (proteins, lipids and entire organelles) are broken down to building blocks by enzymes in the lysosome and the parts are then reused. The enzymatic activity of the lysosome is regulated in part by the ionic composition of the lysosome including the pH, calcium and sodium concentrations. Dysregulation of the lysosome occurs in many lysosomal storage and neurodegenerative diseases. We believe that modulating TRPML1 will restore the activity to the lysosome and health to the affected cells.

TRPML1 normally functions to regulate and maintain this ionic composition, and mutations in TRPML1 lead to Mucolipidosis Type IV, which is typified by lysosomal dysfunction and toxic accumulation of proteins and lipids that have not been efficiently recycled.

Pipeline

Caraway is pursuing multiple small molecule programs focused on genetically validated targets with roles in autophagy and high potential for therapeutic impact. The most advanced of these pipeline efforts focuses on the lysosomal potassium channel, TMEM175. Coding variants of TMEM175 have been linked to both incidence and age of onset of Parkinson’s disease.