Parkinson’s disease (PD) is a progressive and clinically devastating neurological disorder that is typically diagnosed later in life, commonly around 60 years of age, although earlier onset of disease occurs as well. It affects an estimated one million patients in the US and six million worldwide and is expected to double in the next 20 years.

Prior to the onset of disease, an extensive non-motor (prodromal) phase occurs that is characterised by tremors, sleep disturbances, constipation and a loss of sense of smell (anosmia). The progressive and debilitating nature of this disease represents a significant burden to affected patients, their families and support communities.

Research over the past few decades has focused on brain aetiology as the critical target organ. PD is characterised by the deposition of proteinaceous aggregates in the midbrain, known as Lewy bodies, that are enriched in α-synuclein and considered a hallmark of disease. The appearance of these aggregates is associated with a loss of dopaminergic neurons, particularly in the substantia nigra, that are thought to be causal of motor symptoms.

The factors that lead to α-synuclein aggregation and deposition are unclear and may be related to diverse, age-related deficiencies in protein metabolism and clearance. Although its benefit in PD treatment was first described in the early 1960s, levodopa remains a cornerstone therapy. Subsequent research on the neurodegenerative processes associated with PD have led to the identification of new therapeutic targets and candidates, but few of these have transformed patient care. Consequently, the unmet medical need remains significant and new approaches are needed.

Among the newer intriguing target areas is the potential role of the gastrointestinal (GI) tract and its resident microbiota in PD. Several lines of evidence support this concept.

Notably, PD as a pathological cascade may start in the gut, as GI symptoms precede motor deficiencies. Moreover, α-synuclein aggregates have been detected in the gut and shown to migrate to the brain via the vagus nerve. This has led to what is referred to as Braak’s Hypothesis and is supported by animal studies in PD models, where aggregated α-synuclein has been visualised travelling through the vagus nerve from the intestinal endothelium to the brain. Severing of the vagus nerve in these animal models can prevent progression of PD symptoms.

‘Although its benefit in PD treatment was first described in the early 1960s, levodopa remains a cornerstone therapy’

An altered intestinal microbiota, termed ‘dysbiosis’, has been observed in PD patients, and laboratory studies have shown that it is possible for amyloid-type surface proteins from gut microbes to trigger α-synuclein aggregation in vitro.
Limited studies have also shown that the transfer of the intestinal microbiota from PD patients, but not from healthy donors, leads to a more rapid worsening of disease phenotypes in germ-free mouse models of PD. Consequently, one could envision a dysbiotic microbiota over-represented by conditionally pathogenic organisms that could play direct or indirect roles in disease initiation and potentiation.

As with many complex, multifactorial diseases, there are overlaps between PD and other syndromes. Most notably, compelling genetic and pharmacologic relatedness between PD and inflammatory bowel disease (IBD) has been described. For example, mutations in the leucine rich repeat kinase 2 (LRRK2) gene have been identified that are associated with either a risk of developing, or resistance to, IBD.

Alleles mapping to these same regions of the LRRK2 gene have also been associated with PD risk or resistance. IBD is also a risk factor for the development of PD. Most intriguingly, effective treatment of IBD patients with anti-tumour necrosis factor (anti-TNF) agents, which are rapidly becoming the standard of care for this disease, significantly reduces the likelihood of developing PD. Given the established association of a dysbiotic microbiota with IBD, the relatedness to PD suggests that investigating a causative role of intestinal microorganisms in the latter disease is worth considering.

At Artizan Biosciences, we are utilising a novel platform technology to identify microorganisms that may play pathogenic roles in a variety of inflammatory disorders. Based on a platform technology developed by our scientific founders at Yale called IgA-SEQ, this approach enables the identification of gut microbes that have encroached on the intestinal epithelium and engaged the immune system. Such a subset of the microbiota might include organisms that pathogenically affect the functioning of the mucosal barrier, immune system and the enteric nervous system.

Using this approach, we have identified several organisms that are able to disrupt epithelial barrier function in vitro and induce a colitis phenotype in vivo in rodent IBD models. Moreover, these effects are associated with the microbial production of secreted factors that directly affect intestinal barrier integrity in a targeted manner.

Translation of this science towards therapeutic development for patients is underway, and our initial lead molecule, ARZC-001, which specifically inhibits the function of one of these secreted factors is advancing through preclinical IND-enabling studies. If successful, such an approach could offer two important advances in the treatment of IBD patients. First, it could directly address a critical driver of intestinal barrier permeability, promoting epithelial repair. Second, it could offer a personalised medicine approach to the treatment of IBD, since patients harbouring the target organism are readily identified through a PCR assay on a stool sample.

Image shows neurons containing Lewy bodies, small red spheres, which are deposits of proteins accumulated in brain cells that cause their progressive degeneration

Based on our progress towards the development of IBD therapeutics, coupled with the noted overlaps between IBD and PD, Artizan is working to identify microbial drivers of PD and subsequently develop effective, targeted therapies. Notably, a defective intestinal barrier has been implicated in both diseases, suggesting that similar types of identifiable driver organisms exist in the microbiota of PD patients. We are therefore drawing on elements of the IBD programme to design the framework for our PD research.

Critical to the success of the IBD initiative was the creation of a patient stool collection programme which allowed us to interrogate clinically relevant samples for the presence of organisms of interest. We are currently establishing an analogous programme with PD patients that will be bolstered by additional biosampling and data collection efforts. This extensive array of information will allow us to associate patient characteristics with the presence of specific organisms, biomarkers and stages of disease progression.

Of course, complex diseases like PD offer intriguing challenges to the execution of such an endeavour. For example, the sample collection programme will benefit from appropriate patient selection, as we would like to capture individuals who are early in their disease progression given the hypothesis that the GI tract may be the originating organ for this disorder.

In addition, the slow pace of disease progression may require longer studies that would benefit from better prognostic biomarkers. Organisations such as the Michael J Fox Foundation that are actively investigating markers of disease progression may help here, and it is our hope to add to the growing body of knowledge on how disease progresses in this heterogeneous patient population.

The concept of a gut-brain axis is now well-established, with more detailed understanding of specific mechanisms appearing in the scientific literature on a daily basis. In parallel, it is now clear that implicating the GI tract in disease states requires considering the role of the intestinal microbiota as well since they are interdependently intertwined, including both beneficial and pathogenic elements.

We are excited to contribute to our collective understanding of the role of the intestinal microbiota in PD in a deeper and more mechanistically explicit way than has occurred previously, and to answering the tantalising question of whether individual pathogenic microbial strains, ‘hiding in plain sight’, can play initiating or potentiating roles in complex diseases.