Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease

Camilleri, Michael; Subramanian, Thyagarajan; Pagán, Fernando; Isaacson, Stuart; Gil, Ramon; Hauser, Robert A.; Feldman, Mary; Goldstein, Mark R.; Kumar, Rajeev; Truong, Daniel; Chhabria, Nisha; Walter, Benjamin L.; Eskenazi, Jonathan; Riesenberg, Robert; Burdick, Daniel; Tse, Winona; Molho, Eric; Robottom, B.; Bhatia, Perminder; Kadimi, Srinath; Klos, Kevin J.; Shprecher, David; Marquez-Mendoza, Otto; Hidalgo, Gonzalo; Grill, Stephen; Li, George; Mandell, Howard; Hughes, Mary; Stephenson, Sharisse; Vandersluis, Joel; Pfeffer, Michael; Duker, Andrew P.; Shivkumar, Vikram; Kinney, William A.; MacDougall, James E.; Zasloff, Michael; Barbut, Denise

doi:10.7326/m22-1438

Cited by 24 publications

(23 citation statements)

References 30 publications

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“…In an experimental PD model with A53T α-Syn transgenic mice, oral squalamine restored gut motility [ 215 ]. A derivative of squalamine, ENT-01, gave positive results on constipation in PD patients [ 216 ], and the results of a phase 1 clinical trial to evaluate the efficacy in PD dementia are under analysis [ 203 ]. Another aminosterol, trodusquemine, has been tested at the preclinical level to investigate its mechanism of action in inhibiting α-Syn aggregation and its efficacy in animal models [ 217 , 218 ] In artificial membrane, the drug is homogeneously distributed, influencing the lipid raft organization in neuronal membranes and interfering with the start of α-SynO formation [ 219 ].…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson’s disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

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Section: Therapeutic Perspectivesmentioning

confidence: 99%

Alpha Synuclein: Neurodegeneration and Inflammation

Forloni

2023

IJMS

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“…Its administration was safe, and bowel function resulted to be rapidly improved, as well as neuropsychiatric symptomatology, confirming that targeting enteric αS might be a beneficial approach in PD therapy (Hauser et al, 2019). The IIb study KARMET, a randomized and placebo-controlled trial involving another 150 PD patients, was conducted to determine the safety and efficacy of up to 25 days of ENT-01 treatment, confirming its ability to improve both bowel motility and gut-brain axis (Camilleri et al, 2022). Another promising therapeutic approach consists of the enhancement of the degradation of αS misfolded aggregates.…”

Section: Alpha-synuclein-targeting Therapeutic Approachesmentioning

confidence: 85%

α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies

Cecchi¹,

Bigi²,

Cascella³

2023

Neural Regeneration Research

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The misfolding and aggregation of α-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In such conditions, a range of different misfolded aggregates, including oligomers, protofibrils, and fibrils, are present both in neurons and glial cells. Growing experimental evidence supports the proposition that soluble oligomeric assemblies, formed during the early phases of the aggregation process, are the major culprits of neuronal toxicity; at the same time, fibrillar conformers appear to be the most efficient at propagating among interconnected neurons, thus contributing to the spreading of α-synuclein pathology. Moreover, α-synuclein fibrils have been recently reported to release soluble and highly toxic oligomeric species, responsible for an immediate dysfunction in the recipient neurons. In this review, we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused by α-synuclein oligomers and fibrils, both contributing to neurodegeneration in synucleinopathies.

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“…Squalamine is believed to achieve this effect by displacement of membrane bound aggregates of misfolded alpha-synuclein that have altered normal electrical properties. In addition, orally administered squalamine successfully restored gut motility in elderly patients with Parkinson's disease associated constipation in a recently completed Phase 2b clinical trial 30 . We speculate that squalamine reverses the vagal ageing code by displacement of electrically disruptive membrane associated misfolded proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Testing for the response of each of the isolated single units to CCK is a well-established method for identifying vagal bres within the mesenteric nerve bundle 36,37 . Cholecystokinin (25)(26)(27)(28)(29)(30)(31)(32)(33) sulphated (AnaSpec, Fremont, CA, USA) was dissolved in dimethyl sulfoxide (DMSO) to make a 1 mM stock solution. Aliquots were diluted on the day of the experiment to a working concentration of 0.1 µM in Krebs buffer, with a nal DMSO concentration ≤ 0.0001%.…”

Section: Mesenteric Nerve Recordingmentioning

confidence: 99%

Gut-Brain rejuvenation: Identification of age associated changes in the neural firing pattern of myenteric primary afferent neurons and vagal fibres that are reversed by the aminosterol, squalamine

Kunze

Neufeld

Mao

et al. 2023

Preprint

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Vagus nerve signaling is a key component of the gut-brain axis and regulates diverse physiological processes that decline with age. Gut to brain vagus firing patterns are regulated by myenteric intrinsic primary afferent neuron (IPAN) to vagus neurotransmission. It remains unclear how IPANs or the afferent vagus age functionally. Here we identified a distinct ageing code in gut to brain neurotransmission defined by consistent differences in firing rates, burst durations, interburst and intraburst firing intervals of IPANs and the vagus, when comparing young and aged neurons. The aminosterol, squalamine, reverted aged neurons to a young phenotype indicating the age associated changes in neural firing patterns are reversable. In contrast to young neurons sertraline failed to increase firing rates in the aged vagus whereas squalamine was still effective. These results may have implications for improved treatments involving pharmacological and electrical stimulation of the vagus for age-related mood and other disorders.

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Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease

Cited by 24 publications

References 30 publications

Alpha Synuclein: Neurodegeneration and Inflammation

Alpha Synuclein: Neurodegeneration and Inflammation

α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies

Gut-Brain rejuvenation: Identification of age associated changes in the neural firing pattern of myenteric primary afferent neurons and vagal fibres that are reversed by the aminosterol, squalamine

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