Low activity of the lysosomal enzyme glucocerebrosidase (GCase) is associated with increased rate of progression of Parkinson’s disease. Thus increasing GCase activity in the lysosome may slow progression of symptoms. This talk will cover ten years of work on the development of BIA-28, an allosteric activator of GCase: the design and optimization of the molecule, the analysis of its mechanism of action, and the biomarker response of GBA-PD patients to dosing over one month.

Triggering receptor expressed in myeloid cells 2 (TREM2) is a lipid-sensing receptor that promotes the growth, migration, and anti-inflammatory effects of microglia that are upregulated within pathological microenvironments. Loss-of-function TREM2 variants impose genetic risk for Alzheimer’s disease (AD). Herein we highlight the activity and profile of Vigil’s first-in-class small molecule TREM2 agonists for treatment of neurodegenerative diseases.

Alterations in lysosomal function cause detrimental effects including accumulations of toxic cellular waste. These defects have been implicated in diseases from lysosomal storage disorders to more common neurodegenerative disorders. Activating lysosomal function to clear toxic materials and defective cellular components provides a novel strategy for such disorders. Caraway will describe efforts to develop new therapeutics targeting lysosomal transmembrane proteins (TRPML1, TMEM175, ATP13A2) that have been genetically implicated in CNS diseases.

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which, however, have limitations as the inhibited protein can interfere with natural mechanisms which could lead to undesirable side effects. Herein, we present the development of LRRK2 Proteolysis Targeting Chimeras (PROTACs), as an alternative LRRK2 targeting strategy.

Targeted protein degradation allows targeting of undruggable proteins-of-interest for both research purposes and therapeutic applications. We developed the AUTOphagy-TArgeting Chimera (AUTOTAC) degrader platform, which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands that bind p62/Sequestosome-1/SQSTM1. AUTOTACs selectively degraded various high-molecular weight aggregates of amyloidogenic hallmark proteins in neurodegeneration at nanomolar DC50 values in vitro and in vivo, along with improvements in cognition, locomotion and behavior.

TREM2 plays crucial roles in AD by regulating microglia migration toward and phagocytosis of amyloid plaques. By engineering a bivalent TREM2 agonist IgG1 to tetra-variable domain immunoglobulin (TVD-Ig), we increased the TREM2 activation by 100-fold in vitro. A bispecific Ab targeting TREM2 and transferrin receptor (Ab18 TVD-Ig/aTfR) improved Ab brain entry by 10-fold. Treatment of 5XFAD mice with Ab18 TVD-Ig/aTfR showed a considerable reduction of amyloid burden with increased microglia phagocytosis of amyloid plaques, improved synaptic and neuronal marker intensity, improved cognitive functions, and reduced tau hyperphosphorylation. This Ab engineering approach enables the development of potential TREM2-targeting therapies for AD.

Novel delivery solutions are needed to expand the reach of RNAi therapeutics beyond the liver and especially address disorders of the central nervous system. I show that an RNAi therapeutic targeting amyloid precursor protein (APP) mRNA, is able to reduce APP protein expression and thereby reduce both the extracellular b-amyloid as well as intracellular bCTF, a pathogenic metabolite of APP. An overview of our progress on optimization of siRNA conjugated with 2'-O-hexadecyl and delivery to the CNS will be presented.

This presentation covers principles for decision-making and advancing a neuroscience-focused portfolio from small molecule biophysics perspective.

We have reported the discovery and characterization of a novel and specific Caspase-6 inhibitor. This talk will focus on emerging results regarding our second-generation compound in immortalized and iPSC-based tauopathy models. I will also discuss a highly caspase-6 specific cleavage site near the N-terminus of tau that generates a tau fragment which emerging results suggest is more aggregation-prone than full length tau and the tau fragments generated by other caspases.

PINK1 is a central regulator of mitochondrial quality control. Mutations in its gene result in Parkinson’s disease (PD). I will provide updates on MTK458, a molecule we identified that selectively binds PINK1 and promotes mitophagy. MTK458 treatment also drives clearance of pathologic alpha-synuclein, which is known to induce mitochondrial dysfunction, in both in vitro and in vivo models. We have also developed new proprietary assays to probe target engagement and efficacy in vivo. I'll discuss one such assay for the PINK1-pathway marker pS65 ubiquitin (pUb), which we used to show that pUb is increased in idiopathic Parkinson's disease patient samples and decreased following MTK458 treatment in multiple species.