Small molecules quell toxic alpha-synuclein in preclinical studies
Wren Therapeutics says it is 'taking a different approach' in Parkinson's research
Wren Therapeutics has developed oral small molecules that suppress the production of toxic alpha-synuclein protein forms in cellular and mouse models used to study Parkinson’s disease.
The potential first-in-class molecules were designed with Wren’s technology platform to hinder processes involved in the generation of alpha-synuclein oligomers, the small protein clumps thought to be driving neurotoxicity and neuroinflammation in Parkinson’s.
To accurately measure these oligomers, Wren also developed a biomarker test, which the company believes can be used as a tool for both preclinical and clinical research.
“We are taking a different approach to drug discovery, using biophysics to design landmark therapeutics that can address the urgent need for effective drugs for this rapidly expanding neurodegenerative disease,” Bart Henderson, Wren’s CEO, said in a press release.
“We are excited about our progress and the promising initial data … for several oral, small-molecule oligomer inhibitors and for the biomarker technologies we are deploying to measure on-target efficacy in both preclinical and clinical studies,” Henderson added.
The data were shared in a pair of poster presentations at the AD/PD 2023-International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, held March 28-April 1 in Gothenburg, Sweden, and virtually.
In Parkinson’s, a misfolded version of the alpha-synuclein protein clumps up (aggregates) inside nerve cells. These insoluble clumps, or fibrils, form deposits called Lewy bodies that disrupt cellular function and progressively lead to the death of dopamine-producing, or dopaminergic, neurons.
The process of how these fibrils are formed is complex, but involves alpha-synuclein monomers (single molecules) clumping together with a few others to form soluble oligomers, eventually leading to the formation of larger aggregates that can’t be properly cleared.
It has become increasingly recognized that alpha-synuclein in its oligomer form is particularly toxic. In addition to converting into insoluble aggregates, oligomers on their own bind to cell membranes and organelles, disrupting important metabolic and nerve signaling processes.
“[Alpha-synuclein] oligomers are fleeting protein intermediates implicated in the molecular damage and cellular destruction that decimate dopaminergic neurons in Parkinson’s disease,” Henderson said.
Difficult to target
However, it has been a challenge to develop a precise way of targeting them, according to Wren.
That’s because the processes by which alpha-synuclein forms into and disassembles from these oligomers, and how fibrils then feed back to form additional oligomers, is very complex.
“Their elusive, ephemeral physical nature makes them difficult to target using conventional drug discovery approaches, as well as to develop biomarkers to support clinical development,” Henderson said.
Wren’s technology platform enables a closer analysis of oligomer dynamics, thereby informing the discovery of molecules that can precisely block oligomers at the source of their generation, preventing fibril formation.
The company, in collaboration with Eisai, now has conducted preclinical studies to evaluate the potential of orally available small molecules developed using its platform.
In the poster “Reducing toxic alpha-synuclein oligomers in PD through precise targeting of the molecular mechanisms of oligomer formation with small molecule inhibitors,” researchers described the properties of a prototype molecule derived from the platform.
Dubbed WTX-A, the molecule was shown to suppress both primary nucleation, a process that produces oligomers from monomers, as well as secondary nucleation, which feeds back to form oligomers from existing fibrils.
It also was found to be specific for alpha-synuclein, not affecting the aggregation process of other proteins that are known to drive neurodegeneration in other diseases.
WTX-B, a second-generation oligomer inhibitor, was found to have greater potency and better pharmacological properties than WTX-A.
The candidates’ efficacy was then confirmed using the company’s new biomarker assay to detect oligomers.
The development and validation of this assay were discussed in the second poster, “The selective detection of alpha-synuclein oligomers to analyze small molecule inhibitors of their formation for the treatment of Parkinson’s disease.”
“Our objective was to develop a biomarker assay for the selective detection of [alpha-synuclein] oligomers enabling biomarker-driven clinical development of small molecule therapeutics,” the researchers wrote.
Measuring oligomers specifically
The antibody-based assay is designed to specifically measure oligomers, but not monomers or fibrils, using a variety of lab techniques. After validating the assay in the lab for its selective binding to oligomers and to a diverse range of oligomer forms, scientists evaluated its ability to quantify changes in oligomer levels.
The test detected significant reductions in oligomer levels after treatment with one of Wren’s small molecule candidates in both lab-grown healthy dopaminergic neurons and a Parkinson’s mouse model. In the mouse model, this reduction was associated with a corresponding drop in alpha-synuclein aggregates, as assessed with standard methods.
In addition to Parkinson’s disease, Wren believes its molecules may be of benefit for other diseases marked by the accumulation of alpha-synuclein clumps, namely dementia with Lewy bodies and multiple system atrophy.
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