Immunotherapies Targeting α -Synuclein in Parkinson Disease
Background: Parkinson disease (PD) is a progressive neurodegenerative disorder. Pathologic diagnosis of PD relies on loss of dopamine neurons in the substantia nigra and accumulation of the abnormal protein α -synuclein in the form of Lewy bodies and Lewy neurites. Alteration in aggregation properties of this protein is believed to play a central role in the pathogenesis of PD.
Observations: Huge interest has developed in antibody-based therapies for PD. Several studies have tested immunotherapies in PD animal models with the aim of targeting α -synuclein. Immunotherapies can be instituted in 2 ways: active immunization in which the immune system is stimulated to produce antibodies against α -synuclein or passive immunization in which antibodies against α -synuclein are directly administered.
Conclusions: Immunotherapy against α -synuclein has provided a new therapeutic avenue in neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α -synuclein in the pathogenesis of PD in humans.
Passive Immunization
Passive immunization against α-synuclein was first reported by Masliah and colleagues in 2011. A monoclonal antibody against the C-terminus of α-synuclein, 9E4, was injected into a transgenic mouse model of PD. There was reduction in α-synuclein aggregates in the brain along with improvement in motor and cognitive impairment.43 The C-terminus of α-synuclein plays a key role in the pathogenesis of PD. Changes in the C-terminus of α-synuclein induces formation of α-synuclein oligomers and subsequent neuronal spread. Antibody binds to the C-terminus and prevents structural changes that can lead to oligomerization of α-synuclein. Since the first study by Masliah, few other immunization studies utilized different antibodies against the C-terminus of α-synuclein. It was shown in a mouse model that binding of such antibodies promoted clearance of the α-synuclein by microglia.44
Based on these animal studies, Prothena Biosciences (South San Francisco, CA) designed a phase 1, double-blind, randomized, placebo-controlled clinical trial of prasinezumab (investigational monoclonal antibody against C-terminus of α-synuclein), in subjects without PD. The results showed that it was well tolerated, and there was dose-dependent reduction in the levels of free
BIIB054 is another monoclonal antibody that targets the N-terminal of α-synuclein. In animal models, antibodies targeting the N-terminus reduced α-synuclein triggered cell death and reduced the number of activated microglia.48 BIIB054, from Biogen (Cambridge, MA), was studied in 40 healthy subjects and was well tolerated with a favorable safety profile and could cross the blood-brain barrier. Like the prasinezumab study, this also was an ascending-dose study to assess safety and tolerability. In 2018, a randomized, double-blind, placebo-controlled, single-ascending dose study in patients with PD reported that BIIB054 was well tolerated, and the presence of BIIB054-synuclein complexes in the plasma were confirmed.49 A phase 2, multicenter, randomized, double-blind, placebo-controlled study (SPARK) with an active-treatment dose-blinded period, designed to evaluate the safety, pharmacokinetics, and the pharmacodynamics of BIIB054 is currently recruiting patients with PD.
Finally, BioArctic (Stockholm, Sweden) developed antibodies that are selective for oligomeric forms of α-synuclein, which it licensed to AbbVie (North Chicago, Il).50 These antibodies do not target the N- or C-terminus of α-synuclein. Since α-synuclein oligomers play an important role in the pathogenesis of PD, targeting them with antibodies at an early stage may prove to be an effective strategy for removal of pathogenic α-synuclein. Clinical trials are forthcoming.
Conclusions
Immunotherapy against α-synuclein has provided a new therapeutic avenue in the field of neuroprotection. Results from the first human clinical trial are promising, but despite these results, more work is needed to clarify the role of α-synuclein in the pathogenesis of PD in humans. Most of the work concerning α-synuclein aggregation and propagation has been reported in animal models. Whether similar process exists in humans is a debatable question. Similarly, more knowledge is needed about how and where in the human brain antibodies act to give neuroprotective effects. Timing of administration of immunotherapies in real time will be a crucial question.
PD is clinically evident once 80% of dopaminergic neurons in substantia nigra are lost due to neurodegeneration. Should immunotherapy be administered to symptomatic patients with PD, or if it will be beneficial only for presymptomatic, high-risk patients needs to be determined. Like AD trials, not only careful selection of patients, but determination of optimal timing for treatment will be essential. As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.
