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Abstract Details

Small Molecule Inhibitors for Precise Inhibition of Alpha-Synuclein Oligomer Generation in Parkinson’s Disease
Movement Disorders
S32 - Movement Disorders: Trials (3:42 PM-3:54 PM)
002

Oligomeric forms of alpha-synuclein have been shown to have wide-ranging neurotoxicity and underlie the onset and progression of PD. They bind to membranes, receptors and organelles, disrupt metabolic and neuronal functional pathways and ultimately cause neuronal death, but are challenging to target with conventional drug discovery approaches. Using the framework of “chemical kinetics”, we mapped the mechanisms of oligomer generation: primary, lipid-induced nucleation (where lipid membranes catalyse the formation of oligomers by several monomers) and secondary nucleation (where oligomer formation is catalysed by larger alpha-synuclein aggregates).

To develop small molecules which inhibit the key molecular mechanisms responsible for the generation of toxic alpha-synuclein oligomers in Parkinson’s Disease (PD) and other synucleinopathies with precision, from in vitro to in vivo systems.


Compounds were initially characterized in in vitro protein aggregation assays starting from monomeric recombinant human alpha-synuclein. Compounds were then optimised for potency, oral pharmacokinetics and brain penetration. Following this optimisation, compounds were tested in a range of cellular and in vivo systems, including iPSC-derived cortical and dopaminergic neurons, and the Line-61 transgenic mouse model.

Our compounds were able to inhibit both of the key processes generating alpha-synuclein oligomers by >96% in vitro, and retained potency when reactions were seeded with human PD brain tissue. Efficacy was also demonstrated in iPSC derived cells treated with compound, reducing oligomers and pS129 aggregates and improving functional markers. In the Line 61 mouse model, the same compound substantially reduced pS129 aggregate levels (-44% vs vehicle) with on-target reduction of oligomers (-25% vs. vehicle) after dosing at 15 mg/kg for 10 weeks.

Our small molecule inhibitors of alpha-synuclein oligomer generation show a robust effect across systems from in vitro, to cellular and in vivo models, demonstrating both target engagement and functional benefit in translational models.

Authors/Disclosures
John Thomson, PhD (Wren Therapeutics Inc.)
PRESENTER
Dr. Thomson has received personal compensation for serving as an employee of Wren Therapeutics. Dr. Thomson has received intellectual property interests from a discovery or technology relating to health care. Dr. Thomson has received intellectual property interests from a discovery or technology relating to health care.
Andrew Cridland, PhD (Wren Therapeutics) Mr. Cridland has nothing to disclose.
Sarah Ball, PhD (Wren Therapeutics) Dr. Ball has received personal compensation for serving as an employee of Wren Therapeutics Ltd.
Roxine Staats (Wren Therapeutics Ltd.) Dr. Staats has received personal compensation for serving as an employee of Wren Therapeutics Ltd. Dr. Staats has stock in Wren Therapeutics Ltd.
Samata Pandey Dr. Pandey has stock in Wren Therapeutics.
Marta Castellana Cruz Dr. Castellana Cruz has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Wren Therapeutics.
Katarina Pisani Dr. Pisani has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Wren Therapeutics.
Georg Meisl (Wren therapeutics) Dr. Meisl has received personal compensation for serving as an employee of Wren therapeutics. Dr. Meisl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fluidic Analytics. The institution of Dr. Meisl has received research support from ERC. Dr. Meisl has received intellectual property interests from a discovery or technology relating to health care. Dr. Meisl has received publishing royalties from a publication relating to health care.
Isaac Kitchen-Smith, PhD Dr. Kitchen-Smith has received personal compensation for serving as an employee of Wren Therapeutics.
Xiaoting Yang (Wren Therapeutics LTD) Dr. Yang has nothing to disclose.
Benedetta Mannini, PhD (Wren therapeutics) Dr. Mannini has received personal compensation for serving as an employee of Wren therapeutics.
Scott Jeffrey Pollack, PhD (Wren Therapeutics) Dr. Pollack has nothing to disclose.
Luke Rajah, PhD (Wren Therapeutics Limited) Dr. Rajah has received personal compensation for serving as an employee of Wren Therapeutics.
Suzanne Clare Brewerton, PhD (Wren Therapeutics) Dr. Brewerton has received personal compensation for serving as an employee of Wren Therapeutics.
Johnny Habchi, PhD (Wren Therapeutics Ltd) Dr. Habchi has stock in Wren Therapeutics. Dr. Habchi has received intellectual property interests from a discovery or technology relating to health care.
Alleyn Plowright (Wren Therapeutics) Dr. Plowright has received personal compensation for serving as an employee of Wren Therapeutics.