Objective/Rationale: Dln101 is a novel protein from the ghrelin family. Dln101 has several clinical and commercial advantages over ghrelin, which make it a more attractive drug target. In previous studies ghrelin has been shown to protect dopamine releasing cells. Dln101 has been shown to be safe in pre-clinical studies and has been approved for initial trials in humans. The aim of this project is to show that Dln101 has a major impact on the functionality and protection of dopamine neurons.
Project Description:
In previous studies it was shown that the circulating metabolic hormone, ghrelin, protects dopamine neurons during cellular stress and that this effect of ghrelin is mediated, at least in part, by a mitochondrial protein, UCP2. In this study we will determine whether Dln101 functions in a similar manner. We will determine whether Dln101 signaling is an important mechanism by which dopamine cells of pre-clinical models are protected against toxicity induced by a chemical, MPTP, that has effects on the brain mimicking Parkinson’s disease. We will also study the pharmacokinetics and pharmacodynamics of Dln101 in the brain and plasma.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Once Dln-101 is shown to be efficacious in combatting Parkinson’s disease symptoms in pre-clinical models, we plan to move to clinical trials in humans.
Anticipated Outcome:
We plan to provide compelling evidence that Dln-101 is a promising drug for decreasing the vulnerability of dopamine neurons in the course of Parkinson’s disease and for improving the general well being of Parkinson’s patients.
Progress Report
We have shown for the first time that Dln-101 is an effective neuroprotector. It protects dopamine neurons during cellular stress and its efficacy is higher than ghrelin’s. Dln-101’s neuroprotection, similar to ghrelin’s, is UCP2 dependent. Dln-101 was also shown to induce direct activation of dopamine neurons when applied directly to the brain or when injected peripherally (i.p.). The peptides Dln-101 and ghrelin in all studies conducted acted in a similar way with some advantage to Dln-101. Based on the pharmacokinetics and pharmacodynamics studies conducted, we conclude that Dln-101’s profile in plasma is similar to ghrelin’s. Dln-101’s half-life is longer than ghrelin’s, and, in addition, Dln-101 is more stable in plasma.
December 2013