Therapeutic indications

PathMaker Neurosystems has developed a first-in-class neuromodulation platform that is broadly applicable to a number of serious neurological disorders that currently have few effective interventions.  We are working to bring a new treatment modality based on neuromodulation into clinical practice, and expect that our products will offer new non-invasive treatment options for patients with ALS and other serious neurological disorders.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease, Charcot’s disease) is a progressive neurodegenerative disease that affects motor neurons in spinal cord and brain. ALS causes muscle weakness, paralysis, spasticity and eventual death, typically within 2-5 years of diagnosis. While the majority of cases (90-95%) are sporadic and occur in patients without known familial history of ALS, the remaining 5-10% of cases are familial.  ALS affects over 30,000 people in the US, and approximately 450,000 patients worldwide.

Recent research has established important links between ALS and motor neuron hyperexcitability, providing new potential avenues for intervention. In this pathophysiological mechanism, hyperexcitable motor neurons depolarize excessively, become fatigued, and eventually die, leading to weakness and paralysis in the muscles innervated by those motor neurons.  Human nerve conduction testing has demonstrated axonal hyperexcitability of motor neurons in both sporadic and familial types of ALS, and hyperexcitability has been reported in multiple ALS subtypes, suggesting that motor neuron hyperexcitability is found widely across different ALS variants.   Beyond a direct electrophysiological effect on motor neuron excitability after treatment with Multi-Site DCS, we have uncovered molecular level changes that are induced.  We have found that protein levels of NKCC1, a Na-K-Cl cotransporter found on spinal motor neurons and involved in maintaining chloride gradient are elevated in the SOD1-G93A model of ALS and that treatment with Multi-Site DCS reduces NKCC1 protein levels, thereby reducing neuronal excitability.

The formation of protein aggregates in the cytoplasmic compartment of motor neurons is another central feature of ALS pathology.  These typically occur in the form of ubiquitinated inclusions and can contain various proteins, including TDP-43, SOD1, FUS, OPTN and other proteins that get trapped in the inclusions.  These protein aggregates have toxic effects on the motor neuron through toxic gain-of-function or toxic loss-of-function and have prion-like properties. As the toxic effects of TDP-43 and other aggregated proteins are dose-dependent, an intervention that can reduce the presence of pathological cytosolic aggregates could potentially rescue degenerative processes in motor neurons and bring the motor neurons back to a less dysfunctional state.  The two main cellular processes that work to degrade and clear TDP-43 aggregates are the proteasomal degradation and autophagy pathways.  Our pre-clinical studies have shown that we can activate protein degradation pathways following treatment with Multi-Site DCS, resulting in robust reduction of neuronal cytosolic protein aggregates at the site of stimulation.