Targeting neurons in the gastrointestinal tract to treat Parkinson's disease

Abstract

Background Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. Objective We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. Methods In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. Results Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing ( p = 1.2 × 10 −7 ). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was <0.3%. Conclusions Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.

Squalamine and trodusquemine: two natural products for neurodegenerative diseases, from physical chemistry to the clinic

“…The results of the first phase 1/2a clinical trial using squalamine as ENT-01 in an open label study involving 50 patients (RASMET, identifier NCT03047629) have been published. 72 ENT-01 restored bowel motility in over 80% of PD patients with severe constipation. This observation indicates that despite bowel dysfunction in some cases for almost 60 years, the functioning of ENS in PD patients can be restored, and is not, as commonly believed, irreversibly damaged.…”

Gastrointestinal Immunity and Alpha-Synuclein

“…In mid-2018 we completed a 50-patient open label Phase 2a clinical study (RASMET) evaluating ENT-01 for the treatment of constipation associated with PD [50]. ENT-01 is an orally administered synthetic salt of squalamine, a cationic aminosterol originally isolated from the liver and gall bladder of the dogfish shark.…”

New Understanding on the Pathophysiology and Treatment of Constipation in Parkinson’s Disease

“…After taking squalamine in the PD mouse model, the excitability of intrinsic primary afferent neurons of ENS can be rapidly restored (West et al, 2020 ). A double-blind, placebo-controlled study also confirmed that oral tablets of squalamine are safe and significantly improve bowel function in PD-related constipation (Hauser et al, 2019 ). Together, these drugs may provide some promise in clinical trials but need to be evaluated further.…”