RNA Targeted Drug Discovery and Development for Parkinson Disease - Project Summary
Parkinson's disease (PD) is a common, progressive and disabling condition with no cure. Accumulating
evidence from human genetics, cell biology and animal model studies suggest that α-synuclein is a key protein,
as it misfolds and forms fibrils that can propagate across neurons, a phenomenon that can account for the
progressive nature of the disease and the emergence of additional disturbing symptoms including dementia
over time. A strong driver of pathological α-synuclein aggregation is its concentration in the brain, as
individuals with multiplication of the SNCA gene locus develop early onset PD and dementia with a gene
dosage effect. Thus, reducing α-synuclein protein expression is a plausible disease modifying strategy for PD.
This approach targets the root pathogenetic mechanism of the disease and has the potential to mitigate
downstream cascades of pathologic events and slow down neurodegeneration.
Using a series of innovative chemical and cell biologic approaches, we have identified small molecules with
diverse chemotypes that selectively bind to a regulatory element in the SNCA 5' untranslated region, repress
translation, and reduce steady state α-synuclein protein levels leading to cytoprotection. Transcriptome- and
proteome-wide studies show that the lead small molecule, named Synucleozid, is more selective than an
SCNA-directed siRNA. Using Synucleozid as a prototype, we have identified additional diverse scaffolds that
reduce α-synuclein protein levels and have favorable properties for blood-brain barrier penetrance, as defined
by Lipinksi's Rule of 5, properties of CNS drugs, and CNS-MPO calculations.
In this Blueprint Neurotherapeutics project, we will optimize these compounds using a highly tailored
systematic drug discovery and development funnel. In Aim 1 (UG3), we will take a target validation, selectivity,
and in vitro DMPK-driven approach to identify the optimal scaffolds to advance to early stage medicinal
chemistry studies to define structure-activity and structure-property relationships. Using iterative rounds of
optimization, compounds will be evaluated using a comprehensive in vitro and cell-based screening funnel in
preparation for entering the UH3 phase. We will also complete transcriptome- and proteome-wide selectivity
studies in PD patient-derived cells, Subsequent aims (UH3) will include in vivo proof of mechanism, therapeutic
index assessment, and IND-enabling studies, all culminating in a Phase 1 clinical trial.
