Objective: Our goal is to develop small molecules which support and restore nigrostriatal dopamine neurons by activation of glial cell line-derived-neurotrophic factor (GDNF) receptors.

Background: Motor diagnostic symptoms of Parkinson’s disease (PD) are caused by progressive degeneration of dopamine neurons in the brain. GDNF and related proteins protect and restore these neurons in vitro and in animal models of PD, but their clinical translation is complicated. GDNF must be surgically delivered into the brain because it is unable to penetrate through the blood brain barrier (BBB). The brain surgery bears a number of risks and limits the treatment mainly to the moderate and late stage PD patients. Late stage PD patients have little if any dopamine neurons, which can be rescued by GDNF-based treatment, left and, therefore, respond to the treatment poorly. BBB penetrating small molecules targeting GDNF receptors can resolve the delivery issues and can be provided to patients immediately upon diagnosis for disease-modifying treatment. Previously we discovered the first BBB penetrating small molecule (BT13) activating GDNF receptors and having neuroprotective properties in dopamine neurons (1). In the present study we aimed to improve the biological activity of BT13.

Method: We synthesized a series of BT13 derivatives and tested them in a panel of in vitro assays to select the ones targeting GDNF receptors and supporting culturing dopamine neurons. We also assessed the pharmacokinetics and BBB penetration for the top molecules in vivo.

Results: We found several compounds activating RET and RET-dependent signaling in immortalized cells which were able to support the survival of murine midbrain dopamine neurons in culture in nanomolar concentration, thus improving the potency of initial compound BT13 by at least 10 times. Based on PK, biological activity in dopamine neurons and the ability to cross BBB, we selected several candidate molecules for the further tests in animal models of PD which are currently in progress. Preliminary results indicate an improvement in motor performance of PD animals and possibly an increased density of dopamine fibers in the brain.

Conclusion: Targeting RET with small molecules crossing the BBB seems to be promising strategy for the development of disease-modifying treatment against PD.

References: 1. Mahato AK, Kopra J, Renko JM, Visnapuu T, Korhonen I, Pulkkinen N, Bespalov MM, Domanskyi A, Ronken E, Piepponen TP, Voutilainen MH, Tuominen RK, Karelson M, Sidorova YA, Saarma M. Glial cell line-derived neurotrophic factor receptor Rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo. // Mov Disord. 2020 Feb;35(2):245-255. doi: 10.1002/mds.27943

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-the-receptor-of-glial-cell-line-derived-neurotrophic-factor-to-treat-parkinsons-disease/