Immunomodulation for Parkinson Disease

The term neuroinflammation is used frequently, although there is no universally accepted definition. As described in an accompanying review, we define neuroinflammation as a reactive response of immune cells and the mediators they produce (eg, cytokines, chemokines, reactive oxygen species, and other secondary messengers), which cause inflammation of neural tissue.¹ Neuroinflammation may promote α-synuclein (α-syn) aggregation to ultimately cause dopaminergic (DA) cell loss in the substantia nigra with α-syn aggregates, termed Lewy bodies, that are the hallmark of Parkinson disease (PD).² It has been hypothesized that α-syn pathology begins in the gut and travels through the vagus nerve to enter the central nervous system (CNS) at the dorsal motor nucleus, although this has since been debated.³ Brain tissue of patients with PD who underwent fetal nigral transplantation showed increased cytoplasmic α-syn in the transplanted tissue, supporting the theory that α-syn may propagate between cells, similarly to prions.⁴ As aggregation of α-syn and neuroinflammatory effects accumulate, this may cause DA cell loss and subsequent symptoms and signs of PD.⁵ Considering this possible pathogenic mechanism, there are multiple immunomodulators—treatments that enhance or suppress various functional steps in the immune system—under investigation for treating patients with PD,⁶ which we review here. In an accompanying article, we review the evidence for a role of neuroinflammation in PD pathology.

Immunotherapy Targeting α-Synuclein

Because α-syn aggregates in Lewy bodies of PD are a pathologic hallmark of the disease, targeting α-syn has long been considered a potential therapy. Specific monoclonal antibodies targeting extracellular α-syn have been studied (Table). Phase 2 studies using passive immunization (ie, infusion of monoclonal antibodies) against α-syn have been conducted and 1 is continuing into an open-label study, but another has been terminated because primary and secondary targets were not met.^7,8 These antibodies targeted different regions of α-syn. There are also ongoing studies of active immunization again α-syn.⁹

Another drug targeting α-syn, nilotinib, is a breakpoint cluster region (BCR)-Abelson tyrosine kinase (c-Abl) inhibitor that has been approved for use as chemotherapy in chronic myeloid leukemia. Nilotinib helps stop the uncontrolled production of maturing granulocytes (mainly neutrophils). Neuroprotective properties of nilotinib were observed with the potential to inhibit autophagy, aggregation, and propagation of α-syn. In a phase 2 study, however, there was concern regarding poor brain penetration of nilotinib, and it was not effective at delaying disease progression.^10,11 Authors of this study cautioned this does not refute the potential neuroprotective effects of other molecules acting on the c-Abl pathway, and several are under investigation (Table).

Targeting Microglia

Microglia contribute to neuroinflammation through the release of reactive oxygen species (see also Neuroinflammation inParkinson Disease in this issue). Myeloperoxidase generates reactive oxygen species in microglia and has been targeted in clinical trials with the myeloperoxidase inhibitor, AZD3241. In a phase 2 trial, AZD3241 was safe and plausibly decreased microglial activation, suggesting further study is warranted. The phase 3 trial underway, however, is not for PD but rather for multiple system atrophy (MSA), a different neurodegenerative movement disorder also characterized by α-syn pathology.¹²

Targeting Lymphocytes

Azathioprine (AZA) is a systemic immunosuppressant being assessed for treatment of PD in a double-blind, placebo-controlled phase 2 trial, including 60 participants with early PD. As in many other studies, people with other immune conditions are excluded from participation, which may exclude individuals with PD who may be at highest risk for autoimmunity and most likely to benefit from AZA or other immunomodulators.¹³ A small phase 2 clinical trial of 18 participants assessing the use of intravenous fresh frozen plasma from young healthy donors, age 18 to 25 years, has been completed and reported improved cognition in participants with PD and cognitive impairment. Fresh frozen plasma has a number of effects on the immune system, and consists of healthy donor immunoglobulins (IgGs) and other plasma components of plasma (eg, clotting factors). Results have not been published in a peer-reviewed journal, although a press releases stated that use was safe with positive results.¹⁴ The chemokine inhibitor, AKST4290, which inhibits C-C chemokine receptor 3 to prevent recruitment of immune cells is being tested for treatment of PD in a phase 3 trial (Table).

Sargramostim is a human recombinant granulocyte-macrophage colony-stimulating factor that increases T_reg cells and is approved for bone marrow recovery in individuals who had bone marrow transplantation. In a phase 1 trial in people with PD, sargramostim was safe and well-tolerated with modest improvements in the immune profile, through increasing the T_reg cell function and frequency, and motor symptoms as well, although it was a small sample size.¹⁵ No phase 2 trial has been registered with the National Clinical Trials database.

Targeting Cytokines

Various studies suggest immunotherapies that block proinflammatory cytokines, (eg, tumor necrosis factor [TNF] or interleukin [IL]-1 may have protective benefits. Retrospective reviews have shown that although the incidence of PD is higher among patients with ulcerative colitis or Crohn disease, these patients have decreased PD prevalence if exposed to steroids or antiTNF therapy.^16,17 Meta-analysis showed that ibuprofen use was associated with a lower risk of developing PD.¹⁸

The glucagon-like peptide 1 receptor (GLP-1-R) is thought to reduce cellular apoptosis (ie, programmed cell death) that occurs in response to inflammatory cytokines. With the aim of increasing this neuroprotective effect, multiple GLP-1-R agonists are under investigations (Table).¹⁹ This class of medications is approved to treat diabetes. In a phase 2 randomized, double-blind, placebo-controlled, single-site trial, 60 participants with PD were treated with the GLP-1-R agonist exenatide or placebo for 48 weeks followed by a 12-week washout period. Exenatide treatment was safe and improved clinical function as measured with the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor scores compared to placebo.²⁰ A phase 3 study of exenatide is underway, and a phase 2 study assessing safety and efficacy of pegylated exenatide in people with PD has begun. Other GLP-1-R agonists being studied for potential treatment of PD include lixisenatide, liraglutide, and semaglutide.²¹

Targeting the Microbiome

There are a number of ongoing small studies of agents targeting the gut microbiome. The gut-brain axis is complex, and the microbiome affects the immune system through cytokine expression, initiating the adaptive immune system and activating inflammasomes, among other mechanisms. Studies targeting the gut microbiome include, but are not limited to, fecal microbial transplantation, rifaximin, and maltodextrin. A small, open-label of study fecal transplantation, which alters the microbiome, in 15 participants with PD showed improvement of motor and nonmotor symptoms with limited adverse events.²¹ Phase 2 studies in this category are ongoing with many still recruiting.

Targeting Immune- and Parkinson-Related Genes

Leucine-rich repeat protein kinase 2 (LRRK2) mutations are among the most common causes of autosomally dominant inherited PD. LRRK2 is implicated in neuronal and systemic inflammation via lysosomal inhibition. Immune cells express high levels of LRRK2 and some variants of LRRK2 mutation are associated with increased risk of autoimmune inflammatory conditions of the gut.^23,24 There are 2 potent, selective and brain-penetrant small molecule inhibitors of LRRK2 being investigated. Phase I safety data was reported only in news releases that stated all safety and biomarker targets were reached, and that these small molecules will progress to phase 2 trials.²⁵

Conclusion

These studies show there are a number of complex mechanisms in which neuroinflammation is implicated in the pathogenesis of PD. There remain many promising therapeutic trials of immunomodulators. Trials that have been completed with negative results may be, in part, due to suboptimal timing of the administration of the therapy, considering there is significant dopaminergic neuron death by the time patients present with motor symptoms of PD, and neuroinflammation has been implicated at the earliest stages of disease pathogenesis. There are a number of other medications under investigation acting on the immune system aimed at delaying disease progression in PD, and this is not an exhaustive list (Table). Many other immunomodulators have shown promise in preclinical settings, and have yet to reach the bedside of patients with PD.²⁶ Given the various mechanisms in which neuroinflammation leads to disease pathogenesis in PD patients, these medications provide a promising frontier in the treatment of PD.