TMEM175 Program

TMEM175 is a structurally unique lysosomal potassium channel genetically implicated in PD and Lewy Body Dementia.

Loss-of function variants of TMEM175 are associated with increased incidence of PD and earlier age of onset, while gain-of-function variants reduce disease risk.  Experiments in both cellular and transgenic animal models have demonstrated that compromised TMEM175 function leads to destabilized lysosomal pH, reduced activity of key lysosomal enzymes, such as GCase, and increased susceptibility to damage by alpha-synuclein. In addition, increased TMEM175 activity is broadly protective against cellular damage from a variety of insults.

Homozygous loss-of-function mutations in TMEM175 are present in approximately 5% of PD patients, while an additional 20% possess heterozygous loss-of-function mutations. Patients with TMEM175 loss-of-function mutations possess a more severe PD phenotype characterized by earlier age of onset and elevated risk of dementia.

Leveraging our internal high-throughput screening and medicinal chemistry efforts, Caraway has discovered multiple classes of TMEM175 modulators that rapidly and reversibly increase TMEM175 activity, thereby enhancing lysosomal function in cellular models.