A Systems Approach To Parkinson's Disease

By Ben Comer, Chief Editor, Life Science Leader

In August 2023, Gut, a journal published by BMJ, released a study of over 24,000 patients with Parkinson’s disease, finding that certain gastrointestinal disorders — such as difficulty swallowing, constipation, and irritable bowel syndrome (IBS) — might specifically predict Parkinson’s disease. The study aimed to methodically test Braak’s hypothesis, first postulated in 2003, which states that an unknown virus or bacteria in the gut could be a cause of Parkinson’s disease.

For Alex Martinez, CEO and cofounder of Intrinsic Medicine, that study was revelatory. Intrinsic Medicine is currently developing Human-identical Milk Oligosaccharides (HiMO) for the treatment of Parkinson’s disease, a notoriously difficult therapeutic area for drug development. Targeting the microbiome successfully has proven difficult as well, much more so than researchers hoped a decade ago; the startup graveyard is littered with microbiome companies that launched following study results demonstrating that fecal transplant is an effective treatment for C. difficile.

While much remains unknown about the gut-brain axis, evidence is building to support correlations, and potentially even causation, happening between the gut and immune system, and brain disorders. "We don’t know how pervasive they are, and how much a dysregulated system is implicated in disorders that we normally would not associate with gut causality,” says Martinez. Sooner than later, Parkinson’s disease, Alzheimer’s disease, and other dementias could end up being reclassified as clinical features, leading to new subsets of patients, says Martinez. “We are going to understand that the etiology of those diseases is much more ecological, and linear.”

Intrinsic Medicine worked initially to develop HiMOs for a constipation-dominant form of IBS, but was aware of the connection between that disorder and Parkinson’s disease. “There has been a long-standing recognition that Parkinson’s disease patients — up to 80% of whom can present with constipation — have different microbiomes, in terms of the gut and oropharynx,” says Martinez. After the Gut study was published, showing that the risk of Parkinson’s disease in people with a history of constipation-dominant IBS were more than four times higher, Intrinsic Medicine shifted from its open label IBS study into a lead program tackling Parkinson’s disease directly.

HiMOs represent a novel approach in targeting the microbiome due to their multiple modes of action, and ability to remain stable in stomach acid, and to resist enzyme degradation in the upper GI tract. Intrinsic Medicine partnered with infant nutrition company Glycosyn to produce its HiMOs, which are “functionally identical” to naturally produced human milk oligosaccharides. In addition to promoting the proliferation of beneficial gut bacteria, HiMOs regulate immune cells, producing local and systemic anti-inflammatory effects, and strengthen the gut epithelial layer.

Of the microbiome drug development graveyard, Martinez chalks up those failures to the (continuing) mysteries of the gut, as well as investment herd mentality. “Kudos to the early companies that went into the microbiome space … it was like going into an alien world, and then trying to make it do what you want it to do. But you also have to look at those company failures in the context of thematic investment cycles … a bunch of companies were doing slight variations on the same thing, a ton of money got poured in, and then you have outputs of failures, followed by a contraction in the space in terms of funding,” says Martinez.  

What is interesting, however, is that the slope of scientific publications and research coming out “is like a tidal wave, it keeps growing.” When you give microbes in the gut human milk oligosaccharides, they produce metabolites that can pass through the blood/brain barrier, explains Martinez. Identifying new ways to improve gut health could end up solving a host of problems not strongly associated with the gastrointestinal system.

To improve the health of a fishery, for example, start with water quality. The future of treating diseases like Parkinson’s and Alzheimer’s could end up being an ecosystem treatment; in that sense, the gut is “upstream of the central nervous system,” says Martinez.