Guest Commentary: Targeting α-synuclein and the pathogenesis of Parkinson’s disease

Discovery of antibodies highly selective for toxic α-synuclein conformations may require more than just classical methods if pharma and life sciences want to make faster progress against Parkinson's disease

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Targeting α-synuclein and the pathogenesis of Parkinson’s disease
Dr. Neil Cashman of  ProMIS Neurosciences
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the death of dopaminergic neurons in the midbrain (pars compacta area of the substantia nigra) and the formation of inclusions known as Lewy bodies (hallmark lesions of PD), which primarily contain toxic, aggregated α-synuclein. Symptoms do not occur in PD until 80 percent or more of the capacity to produce dopamine is lost. PD is the second most common neurodgenerative disease after Alzheimer's disease, affecting an estimated 10 million people worldwide and ranging in severity from mild to severe.
Carbidopa-levodopa (L-dopa) and dopamine agonists are the standard symptomatic treatments for moderate to severe PD. Administration of L-dopa increases dopamine production by the remaining midbrain neurons and usually provides effective relief of motor symptoms for several years. However, treatment with L-dopa has no beneficial effect on the underlying pathogenesis. As neuronal death continues unabated, the effectiveness of ever-higher doses of L-dopa declines, motor symptoms of PD re-emerge and worsen and new, iatrogenic motor symptoms appear, caused by chronic L-dopa therapy. No available treatment has been proven to slow, halt or reverse the progressive neurodegeneration of PD that ultimately leads to death.
Toxic α-synuclein aggregates in the pathogenesis of PD
The cause of the neurodegeneration in PD was not understood until recent years, when specific forms of α-synuclein were found to be toxic to neurons. Strong genetic, neuropathological and preclinical model evidence suggests that misfolded α-synuclein aggregates into oligomers, comprising the toxic species that plays a central role in the pathogenesis of PD. α-synuclein oligomers are distinguished from monomers and insoluble fibrils, which are not toxic to neurons.1 Pathogenic mechanisms of α-synuclein oligomers include general cellular toxicity, mitochondrial stress, synaptic dysfunction and compromised cell membrane integrity, among others. Furthermore, a large and convincing body of evidence also shows that α-synuclein oligomers act as seeds for the formation of larger aggregates, which acquire the ability to propagate from cell to cell in a prion-like manner, spreading the pathology.
Soon after the discovery of its pivotal role in the pathogenesis of PD and related synucleinopathies, including dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), α-synuclein aggregation became a lead target for PD therapeutics development. A wide range of development strategies have emerged. Because protein misfolding and formation of α-synuclein aggregates occurs very early in PD, initiating anti-α-synuclein treatment in prodromal or early-stage disease is expected to be advantageous and could prevent the inevitable extensive neurodegeneration.
Early-stage clinical trials
Early-stage human clinical trials with developmental anti-α-synuclein therapies are underway. Biogen and Prothena Therapeutics/Roche are developing immunotherapies based on antibodies aimed at targeting and inactivating misfolded alpha-synuclein. Both programs are in Phase 2 testing in people with early PD. AstraZeneca/Takeda are testing an α-synuclein antibody in Phase 1 in healthy volunteers.
Other approaches have reached early-stage clinical testing. Affiris has completed a series of Phase 1 trials, including long-term immunogenicity assessment, with a vaccine designed to stimulate production of α-synuclein antibodies. Neuropore and UCB are developing a small-molecule α-synuclein misfolding inhibitor to interfere with propagation of protein aggregates and have completed a Phase 1 study in healthy volunteers. Proclara Biosciences is developing a compound that binds to α-synuclein, amyloid-beta and tau and is in Phase 1 in people with mild to moderate probable Alzheimer's disease. Drugs that are not specific to α-synuclein but proposed to have mechanisms of action that decrease α-synuclein toxicity (e.g., inhibit cell-to-cell transmission, promote autophagic degradation) are in early-stage clinical development, primarily by academic institution sponsors.
Early-stage clinical trials are undertaken, principally, to determine the safety and dosing of developmental compounds. Traditionally, efficacy is not a primary outcome measure until late-stage trials. However, biomarkers for predicting the efficacy of developmental α-synuclein therapeutics are currently undergoing evaluation and validation. If successful, they might soon enable drug developers to reach go/no-go decisions based on anticipated efficacy before investing in long and costly Phase 3 trials. Which of the current drugs in development, if any, might eventually be approved by FDA will be determined by Phase 3 efficacy trial results, which will not be available for at least several years.
Preserving normal, physiological α-synuclein tetramer
During the last decade, a novel α-synuclein species designated the helical tetramer was recognized, which is stable and performs an important physiological function by inhibiting α-synuclein aggregation.2 More recently, a transgenic mouse model designed to make mice unable to form the physiological tetramer resulted in the development of a disease closely resembling human PD.3 These findings have important implications for α-synuclein-based therapeutics development. If the tetramer must be preserved to maintain normal α-synuclein homeostasis, what will be the effects of therapeutics designed to attack all α-synuclein conformations, including the tetramer? Will these drugs be efficacious and without adverse effects (AE)? Or will the inactivation of α-synuclein tetramer compromise efficacy or cause AEs?
It is important to understand that protein misfolding, leading to the formation and aggregation of toxic oligomeric conformations and propagation (prion-like, cell-to-cell transmission) of toxic oligomeric aggregates, is not unique to PD, DLB and MSA. This pathogenic mechanism is implicated as an underlying cause of most neurodegenerative disorders, including PD, DLB and MSA (all three are synucleinopathies), Alzheimer's disease (AD, aggregation of Aβ and tau are the characteristic proteins), amyotrophic lateral sclerosis (ALS, aggregation of TDP43 and SOD1), frontotemporal dementia (FTP; TDP43 and tau aggregation) and others.
In AD, although amyloid beta (Aβ) exists in many different conformations, only specific (low molecular weight) Aβ oligomers (AβO) are toxic.4 The many late clinical-stage failures of developmental anti-Aβ therapeutics are directly attributable to targeting non-toxic conformations of the Aβ protein, while failing to target, or ineffectively targeting, the toxic species, AβO. For α-synuclein oligomers, it is currently unclear which molecular species are toxic. It is presumed that avoidance of α-synuclein physiological tetramers should be avoided, but that other oligomers (including misfolded tetramers and protofibrils) are contributing to the pathological spread of the α-synucleinopathies. Therefore, the development of an anti-α-synuclein therapeutic with maximal efficacy is expected to require antibodies (or other approaches) that are highly selective for the toxic forms of α-synuclein (oligomers and/or small soluble fibrils), while sparing normal, physiological forms (α-synuclein tetramer) and inert species (monomers) to minimize the likelihood of adverse events.
Discovery of antibodies highly selective for toxic α-synuclein conformations
The application of classical methods for the discovery of anti-α-synuclein antibodies yields pan-α-synuclein antibodies that bind all species of the α-synuclein protein. Discovery research of anti-α-synuclein antibodies with highly selective binding profiles for only the toxic forms, while sparing the physiological and inert forms, is challenging. Toxic oligomers contain unstructured regions and are unstable. However, misfolding results in the formation of new epitopes in the misfolded α-synuclein aggregates; and, critically, the toxic conformations are preserved during the corruptive protein templating process by which prion propagation and cell-to-cell spread occur. Scientific literature suggests a complex binding profile for such an antibody.
For its part, ProMIS Neurosciences has developed a unique antibody design platform to identify an optimal “disease selective” binding profile suggested by the scientific literature, “tune” epitopes to generate antibodies with desired binding profiles, and then assess functional performance and comparative binding to select a lead candidate. Application of this discovery platform to α-synuclein and the synucleinopathies led to the generation and development of highly selective antibodies that target only the toxic forms of α-synuclein, toxic oligomers and/or small soluble fibrils, while avoiding the targeting of physiological tetramers and inert monomers. These antibodies achieved the targeted binding profile for treating PD, demonstrating effective neutralization of toxic oligomers and cell-to-cell spread of soluble fibrils, while sparing the physiological forms of α-synuclein such as monomers and helical tetramers. Such antibodies would be expected to treat PD and other α-syncleinopathies without adverse effects.

Neil Cashman, M.D., is chief scientific officer and co-founder of ProMIS Neurosciences Inc.
1. Brundin P, Dave KD, Kordower JH. Therapeutic approaches to target alpha-synuclein pathology. Exp Neurol. 2017;298(Dec, pt B):225-235.
2. Bartels T, Choi JG, Selkoe DJ. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011;477(7362):107-10.
3. Nuber, etal. Abrogating Native a-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease. Neuron 2018;100:75–90.
4. Yang T, Li S, Xu H. Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate. J Neurosci. 2017;37:152-163.

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