Assessing Immunotherapies Targeting α-Synuclein in Parkinson Disease

Parkinson disease (PD) is characterized by the loss of dopamine neurons in the substantia nigra and accumulation of α-synuclein, an abnormal protein suggested to have a central role in the pathogenesis of PD.

In a review published in Federal Practitioner, author Fariha Jamal, MD, noted that substantial interest has developed in antibody-based therapies for PD, with several PD animal model studies aiming to target α-synuclein. Jamal outlined the progress so far within immunotherapy against this protein.

In first explaining α-synuclein, Jamal said that accumulation comes in the form of Lewy bodies and Lewy neurites which both gather within the substantia nigra, as well as other brainstem nuclei and cerebral cortex. It is in the alteration of aggregation properties for α-synuclein where the risk of PD may be heightened. “α-synuclein aggregates may be released into extracellular spaces to be taken up by adjacent cells, where they can cause further misfolding and aggregation of protein,” said Jamal.

As referenced, prior animal models have examined α-synuclein, which led to suggestions of a prion protein-like spread of α-synuclein. “This finding can have long-term therapeutic implications, as preventing extracellular release of abnormal form of α-synuclein will prevent the spread of pathologic protein. This can form the basis of neuroprotection in patients with PD.”

So, how can immunotherapies target α-synuclein?

As Jamal highlights, immunotherapies can be instituted in 2 ways:

• Active immunization where the immune system is stimulated to produce antibodies against α-synuclein
• Passive immunization in which antibodies against α-synuclein are directly administered

Jamal notes that active immunization was examined by AFFiRiS, an Austrian biotechnology company who developed 2 peptide vaccines PD01A and PD03A. In the first human clinical trial examining PD01A, 32 subjects with early PD were randomized to receive either 4 low- or high-doses of the immunotherapy PD01A or placebo. In these phase 1 study findings, the vaccinations were found to be safe and showed a clear immune response against the peptide and crossreactivity against α-synuclein targeted epitopes.

Further success within active immunization was shown in results of the AFFiRis Phase 1 trial on PD03A as it showed a clear dose-dependent immune response of the vaccine against the peptide and cross-reactivity against α-synuclein targeted epitope.

For passive immunization against α-synuclein, Jamal says that a phase 2, multicenter, randomized, double-blind, placebo-controlled study named SPARK, is currently recruiting patients with PD to examine the safety, pharmacokinetics, and the pharmacodynamics of a monoclonal antibody (BIIB054) that targets the N-terminal of α-synuclein.

In concluding, Jamal says that immunotherapy against α-synuclein has provided a new therapeutic avenue in neuroprotection, but that more work is needed to clarify the role of the protein within pathogenesis of PD in humans. “As the understanding of PD pathogenesis and therapeutics evolves, it will become clear whether immunization targeting α-synuclein will modify disease progression.”

Reference

Jamal F. Immunotherapies targeting α-synuclein in Parkinson disease. Fed Pract. 2020; 37(8): 375–379. doi:10.12788/fp.0026