De-risking Therapeutic Development for Key Endolysosomal Targets: TRPML1, TMEM175 and ATP13A2

Summary of Target and Rationale for Funding:

TRPML1, TMEM175 and ATP13A2 are lysosomal ion transporters involved in pathways associated with Parkinson’s disease (PD) pathogenesis. These transporters play roles in maintaining lysosomal homeostasis, autophagy and mitochondrial integrity, which are important for clearing alpha-synuclein and damaged organelles. Impaired TRPML1 function can affect lysosomal trafficking and exocytosis, while TMEM175 variants influence lysosomal pH and protease activity, and ATP13A2 mutations impact polyamine and metal ion transport. Genetic analyses have identified associations between TMEM175 and ATP13A2 variants and PD risk, and TRPML1 dysfunction is linked to alpha-synuclein accumulation. These findings suggest that lysosomal dysfunction is relevant to neurodegeneration in PD and indicate potential areas for therapeutic development. There are currently several active industry programs focused on these targets.

Key Gaps to Address:

Translating TRPML1, TMEM175 and ATP13A2 into clinical therapies for Parkinson’s disease is limited by three key gaps: (1) Pre-clinical models and mechanistic understanding remain incomplete, as current systems do not fully mimic human PD biology or capture the subtle effects of genetic risk variants; (2) Translational endpoints are lacking, with few robust readouts directly linking lysosomal ion channel/ATPase modulation to neuronal health; and (3) Clinical biomarkers for lysosomal dysfunction, target engagement and patient stratification are underdeveloped. Addressing these gaps with better models, mechanistic clarity and biomarker-driven strategies is essential for moving these promising targets into the clinic.

Steps to Address Gaps:

With help from our scientific advisors, we have developed a top-down strategy that will address the key bottlenecks across these targets:

1. Establish robust mechanistic endpoints in lysosomal, lipid and mitochondrial biology through bi-directional modulation of the targets in endogenous cellular models to:

• Validate known mechanisms by which these targets potentially contribute to PD
• Develop robust and standardized endpoints for future testing of therapeutic activators

In-vitro team:

• Wade Harper, Harvard University, Abu Remaileh Monther, Stanford University, Luis Bonet Ponce, The Ohio State University, Peter Vanghleuwe, KU Leuven, Loren Looger, University of California San Diego, & Christian Grimm, Oxford University: Toward an Atlas of Endolysosomal System Dysfunction with PD-associated Channels/Transporters

Contributing tools

• Casma Therapeutics

2. Establish robust translational endpoints in lysosomal, lipid and mitochondrial biology through bi-directional modulation of the targets in in-vivo models to:

• Enable therapeutic testing of activators
• Identify translational biomarkers for assessing target and pathway engagement

In-vivo team:

• Miratul Muqit, University of Dundee, Abu Remaileh Monther, Stanford University & Peter Vanghleuwe, KU Leuven: Proteomic and lipidomic analysis of lysosomes and mitochondria of PD-associated endolysosomal genes
• Paul Wes, Bexorg: Development of translational biomarkers for TRPML1 target engagement in intact whole human Parkinson’s disease brains
• Jacob Erikson, Ninesquare: In vivo efficacy of a TRPML1 activating compound in a-Synuclein PD mouse models
• Leon Murphy, Casma Therapeutics: Development of in vivo biomarker for TRPML1 target engagement and analysis of therapeutics

Contributing tools

• Casma Therapeutics
• Tenvie Therapeutics

3. Establish infrastructure for clinical samples collections and biomarkers of TMEM175 and ATP13A2 for:

• Identifying potential patient population who would be responsive to TMEM175 therapeutic activators

Biomarkers team:

• Peter Vangheluwe, KU Leuven, Christine Klein, University of Lubeck, & Esther Sammler, University of Dundee: A cohort of ATP13A2 carriers for clinical and biomarker analysis
• Grzegorz Kudla, University of Dundee & Katie Headland, Axxam: Deep mutational scanning of TMEM175
• Ziv Gan-Or, McGill University & Edward Fon, McGill University: Exploring TMEM175 as a key target in the pathogenesis of Parkinson’s Disease

The initiative will develop a suite of tools to advance research, including iPSCs and pre-clinical models, for studies investigating disease variants and pathway alterations. Additionally, the program will support knockout validation of antibody reagents to support studies in TRPML1, TMEM175 and ATP13A2. All tools and tool validation data will be made openly available to the research community. Within the Targets to Therapies Initiative, teams will utilize key clinical samples from PPMI and a newly assembled ATP13A2 cohort biosample collection.