Parkinson’s Disease

Targeting Alpha-synuclein, the Major Driver of Parkinson’s Disease

Research gathered from numerous genomic analyses, cell cultures, and in vivo studies indicates that alpha-synuclein (α-Syn) plays a major role in the development of Parkinson’s disease (PD) and other neurodegenerative disorders. In particular, soluble aggregates such as oligomers and soluble fibrils represent the most pathogenic forms of α-Syn.

About Parkinson’s

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons located in the midbrain and the presence of intraneuronal inclusions (Lewy bodies/Lewy neurites) consisting mainly of aggregates of α-Syn. Accumulation of insoluble α-Syn fibrils in the brain has also been observed in dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Progression of PD is likely facilitated by misfolded oligomers and small soluble fibrils of α-Syn that have been shown to propagate from cell to cell in a prion-like manner in both in vitro and in vivo studies.

Misfolded Protein Targets for Parkinson’s

Misfolded Protein Target Lead Indication Other Indications Status
Alpha-synuclein Multiple System Atrophy Parkinson’s, DLB Lead Antibodies

α-Syn Program Key Features

Our technology platform has created antibodies with potentially greater selectivity for only toxic misfolded of α-Syn.

  • No binding to monomers
  • No binding to physiological tetramers
  • Binding to pathogenic oligomers/small soluble fibrils
  • Binding to native toxic α-Syn in PD/DLB brain extract
  • Little or no binding to insoluble fibrils (Lewy bodies)

Screening and Validation for PD Candidates

Identifying Highly Selective α-Syn Antibodies

Our proprietary computational platform was used to identify epitopes that are exclusively exposed on the surface of toxic misfolded species of α-Syn, in a shape (conformation) distinguishable from that of monomers, physiological tetramers, and insoluble fibrils (Lewy body/Lewy neurites).

These conformational epitopes were then used for immunization and generation of monoclonal antibodies that exhibit selective binding to the toxic forms of α-Syn, as demonstrated via several methods, including surface plasmon resonance, immunohistochemistry, and dot blot analysis.

Overcoming Hurdles Associated with Achieving α-Syn Molecular Selectivity

α-Syn proteins pose a difficult challenge for molecular species selectivity. There are six molecular species of α-Syn in total, two of which are physiologically important and should be avoided, and two that are toxic and should be targeted.

Only α-Syn antibodies generated using our proprietary discovery platform can selectively target the toxic oligomers and inhibit α-Syn propagation while leaving healthy, physiologic oligomers unaffected. Thanks to our unique platform, we have achieved these results with multiple antibodies, created with different conformational epitope predictions, thereby demonstrating the unrivaled power of our technology.

Development Status

The next step is selection of a lead candidate targeting misfolded alpha-synuclein for humanization and producer cell line development.

Our Lead Program: PMN310 for Alzheimer’s

PMN310 selectively binds to the toxic misfolded forms of amyloid-beta, a protein commonly associated with the development of Alzheimer’s disease. Compared to other amyloid-focused antibody therapies currently in development, initial studies of PMN310 indicate greater selectivity in binding to the toxic misfolded oligomers of Aβ protein.

TDP-43 Antibody Therapies for ALS

Misfolded TAR DNA-binding protein 43 (TDP-43) plays a key role in the development and progression of amyotrophic lateral sclerosis (ALS). Our ALS therapeutic programs target only the toxic misfolded forms of TDP-43 and not its physiologic forms, which are essential for normal neuronal cell function.

Posters & Publications

Our scientific expertise is backed by decades of research on protein misfolding diseases such as AD, ALS, and PD. We encourage you to visit our scientific library to learn more about our programs.

View Posters and Publications