Small-molecule binders of LAMP2A for monitoring lysosomal function in lysosomal storage disorders

Overview

Lysosomal storage disorders (LSDs) are caused by genetic defects that lead to harmful accumulation of metabolites inside lysosomes, resulting in cellular dysfunction and cell death. A common underlying issue across multiple LSDs is the decreased expression and impaired trafficking of LAMP2A, the lysosomal receptor responsible for chaperone-mediated autophagy (CMA). This research proposes a novel strategy: using small-molecule binders that specifically recognize the unique cytosolic tail of LAMP2A to monitor lysosomal function and predict cellular response to therapies. Unlike current approaches that track metabolite accumulation, this method provides insight into the actual functional health of lysosomes, offering a more meaningful biomarker for disease progression and treatment efficacy in LSDs such as cystinosis and mucolipidosis, as well as in metabolic disorders and neurodegeneration.

Technical specifications

Key features:

• Small molecules designed to bind the 11-amino-acid cytosolic tail of LAMP2A, a region that is flexible and exposed to the cytosol
• Compounds identified through in-silico screening using PyRx, with preliminary validation confirming that binders can be found
• Specificity validated using wild-type cells, LAMP2A-knockout cells, and LSD cell models
• Potential for in vivo application in disease models with and without therapeutic intervention
• Based on the structural understanding that LAMP2A forms a homotrimer with membrane-spanning helices in a parallel coiled-coil conformation

How it works:

The small molecules interact with the cytosolic domain of LAMP2A, enabling detection and monitoring of LAMP2A levels and localization at the lysosomal membrane. This provides a functional read-out of CMA activity that is independent of metabolite accumulation, addressing limitations of current therapies such as cysteamine, which reduce lysosomal overload but do not restore LAMP2A function.

Technology readiness level

This technology is currently at an early-to-mid stage of development. The research team has demonstrated proof-of-concept for LAMP2A mislocalization as a contributor to LSD pathophysiology and has completed initial in-silico identification of candidate small-molecule binders. Preliminary data from a small compound library confirms that functional binders can be identified. Up to five lead compounds are slated for specificity validation in wild-type, LAMP2A-knockout, and LSD cell models. Future work will include in vivo testing in relevant disease models, with and without existing therapies, to advance toward translational application. The approach represents a novel diagnostic and monitoring strategy that could complement or improve upon existing LSD treatment paradigms.