It’s All Connected
If the scientific community wants to tackle neurological disorders, it needs to shift its focus beyond the brain – the gut also plays a role.
Maryam Mahdi | | Longer Read
Do neurological disorders begin in the brain or elsewhere? Mounting research now points to the enteric nervous system (ENS) – our second brain – in the onset of central nervous system (CNS) disorders like Parkinson’s Disease (PD). The ENS has an extensive connection to the brain and is integral to gastrointestinal function. Some biotech companies, such as Axial Biotherapeutics, are beginning to explore the gut-brain axis for the development of novel therapeutics for diseases and disorders affecting the CNS. Axial was founded in 2016 to pursue non-traditional approaches to treating CNS diseases by targeting the gut rather than the blood-brain barrier to treat disease.
“The direction in which we took the company went against the doctrines taught in medical schools for decades, i.e. treating CNS diseases by developing systemically available drugs that cross the blood brain barrier,” says David H. Donabedian, co-founder and CEO of Axial Biotherapeutics. “Today, we have a pipeline of candidates that target the gut and the gut-brain axis, contrary to these mainstream approaches.”
Axial believes that certain diseases, e.g. PD and Autism Spectrum Disorders (ASD) may emanate via the gut and the gut microbiome. Since 2015, approximately 15 publications have established that the PD microbiome is different from matched healthy controls; and certain types of bacteria are elevated in the PD microbiome. In PD, many non-motor symptoms, including constipation, loss of smell (hyposmia) and trouble swallowing (dysphagia) precede motor symptoms by years. Braak’s hypothesis helps explain the connection between the gut and brain and resulting disease progression in PD. The hypothesis states that pathogens enter the body via the nasal cavity, reaching their final destination in the gut where they cause the aggregation of abnormal proteins, Lewy bodies, in nerve cells contributing to sporadic PD, the most common form of the disease. The buildup of Lewy bodies also impairs the enteric nervous system resulting in changes in gut transit time, which can lead to unpleasant non-motor symptoms, including constipation, dysphagia and hyposmia.
“The gut microbiome promotes the normal development of the ENS and may help modulate GI function,” explains Donabedian. “The resident microbiome can, therefore, influence host homeostasis and, when unbalanced, may trigger the non-motor symptoms experienced by PD patients.”
Axial’s lead candidate, AB-4166, is a small molecule drug that stops Lewy body aggregation and is currently being evaluated for safety and tolerability in a subset of PD patients. Axial’s PD program has also identified multiple novel chemical entities in the AB-4000 series which are being developed to have improved selectivity as potential next-generation drug candidates for PD and other neurodegenerative diseases.
In addition to PD, Axial is interested in the microbiome’s ability to influence ASD. The company is focused on understanding the role of microbial based metabolites in specific ASD patient subgroups. Though it is understood that we all are different and therefore have differences in our gut microbiome and microbiome-based metabolites, when compared with neurotypical children, certain ASD children tend to have less overall abundance and diversity in their microbiome, which results in an altered microbiome-based metabolite. Donabedian explains that this change may be attributed to many factors, including a leaky gut phenotype. A leaky gut may allow for certain molecules to pass through the GI tract that normally would not have access and may also allow oxygen to enter the gut and alter the resident microbiome profile, further exacerbating GI symptoms like diarrhea, constipation and abdominal pain.
Axial has developed, AB-2004, a gut retentive small molecule that has demonstrated, in animal models, the ability to repair leaky gut and improve repetitive behavior, anxiety, and ASD-related sensorimotor gating deficits by removing key microbial metabolites. “Our preclinical studies and cross-sectional data in ASD children support that certain metabolites are overrepresented in subsets of autistic children,” says Donabedian.
Regulators are keen to support companies who are developing microbiome-targeted small molecules. Unlike companies chasing fecal microbiome transfer approaches, which pose unique challenges for regulators because they are so different to traditional drug products, such companies are creating small molecules with similar characteristics to those already used for the treatment of CNS disorders.
Axial recently announced a collaboration with Taiho, a Japanese pharmaceutical company focused on the development of treatments for cancer. The partnership will give the Japanese company access to Axial’s platform for the discovery and development of novel compounds for oncology therapeutics. Though therapeutics like immunotherapies are massively changing patient outcomes, these outcomes are often heterogeneous, and existing biomarkers do not accurately predict patient response. Microbiome-targeting therapeutics for oncology offer the pharmaceutical industry new ways to combat cancer and may be manipulated to better fit patient needs.