TRPML1 Program

TRPML1 is a member of the Transient Receptor Potential ion channel superfamily.

The channel is located primarily on lysosomes, which serve as the recycling centers within a cell. Cellular components (proteins, lipids, and whole 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 activity to the lysosome and health to the affected cells.

TRPML1 normally functions to regulate and maintain the ionic composition in the lysosome, 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.

1) Stimulating TRPML1 can drive clearance by enhancing activity of multiple lysosomal enzymes

2) TRPML1 activation can impart longer term cellular changes by impacting gene transcription

3) Ca2+ release through TRPML1 can stimulate membrane repair and recycling via lysosomal fusion with the plasma membrane



TRPML1 Modulators for GBA-PD


Homozygous loss-of-function mutations in the gene encoding glucocerebosidase (GBA) cause the lysosmal storage disorder, Gaucher disease. Heterozygous variants in GBA are the most significant genetic risk factor for the development of Parkinson’s Disease (PD).

GBA-Parkinson’s Disease (GBA-PD) is one of the most common genetically-defined forms of PD, accounting for approximately 10% of all PD (~100,000 U.S. patients and ~700,000 patients worldwide). Patients with GBA-PD typically have a more severe disease phenotype characterized by earlier age of onset, more rapid disease progression, and increased risk of dementia relative to individuals with idiopathic PD.

In addition to general enhancements of lysosomal function, Caraway has demonstrated that TRPML1 activation leads to enhanced expression and activity of glucocerbrosidase, augmenting a key lipid processing pathway that is compromised in GBA-PD patients.

Caraway is developing proprietary small molecule TRPML1 modulators for the treatment of GBA-PD and other neurodegenerative diseases.


TRPML1 Modulators for Genetically-defined Rare Diseases

Many genetically-defined rare diseases are caused by peturbations of lysosomal function.  In addition to the more than 50 monogenetically defined lysosomal storage disorders, there are a variety of diorders typified by lysosomal dysfunction due to alterations in other cellular signaling pathways.  These include diseases that impact the muscle, heart, liver, and kidney.  Caraway is developing proprietary small molecule TRPML1 modulators for the treatment of diseases that affect these organ systems.